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Molecular machines in biology

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1 Molecular machines in biology on Tue Nov 12, 2013 4:25 pm


Molecular machines in biology

The concept of molecular machines in biology has transformed the medical field in a profound way. Many essential processes that occur in the cell, including transcription, translation, protein folding, and protein degradation, are all carried out by molecular machines.

Proteins are the machinery of living tissue that builds the structures and carries out the chemical reactions necessary for life. For example, the first of many steps necessary for the conversion of sugar to biologically-usable forms of energy is carried out by a protein called hexokinase. Skin is made in large measure of a protein called collagen. When light impinges on your retina it interacts first with a protein called rhodopsin. As can be seen even by this limited number of examples proteins carry out amazingly diverse functions. However, in general a given protein can perform only one or a few functions: rhodopsin cannot form skin and collagen cannot interact usefully with light. Therefore a typical cell contains thousands and thousands of different types of proteins to perform the many tasks necessary for life, much like a carpenter's workshop might contain many different kinds of tools for various carpentry work.

What do these versatile tools look like? The basic structure of proteins is quite simple: they are formed by hooking together in a chain discrete subunits called amino acids. Although the protein chain can consist of anywhere from about 50 to about 1,000 amino acid links, each position can only contain one of twenty different amino acids. In this way they are much like words: words can come in various lengths but they are made up from a discrete set of 26 letters. Now, a protein in a cell does not float around like a floppy chain; rather, it folds up into a very precise structure which can be quite different for different types of proteins. When all is said and done two different amino sequences--two different proteins--can be folded to structures as specific as and different from each other as a three-eighths inch wrench and a jigsaw. And like the household tools, if the shape of the proteins is significantly warped then they fail to do their jobs.

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2 Molecular Machines in the Cell on Wed May 06, 2015 10:35 am


Molecular Machines in the Cell

Molecular Machines in the Cell
Casey Luskin
Discovery Institute
June 11, 2010
Print Article
Long before the advent of modern technology, students of biology compared the workings of life to machines.1 In recent decades, this comparison has become stronger than ever. As a paper in Nature Reviews Molecular Cell Biology states, “Today biology is revealing the importance of ‘molecular machines’ and of other highly organized molecular structures that carry out the complex physico-chemical processes on which life is based.”2 Likewise, a paper in Nature Methods observed that “[m]ost cellular functions are executed by protein complexes, acting like molecular machines.”3

A molecular machine, according to an article in the journal Accounts of Chemical Research, is “an assemblage of parts that transmit forces, motion, or energy from one to another in a predetermined manner.”4 A 2004 article in Annual Review of Biomedical Engineering asserted that “these machines are generally more efficient than their macroscale counterparts,” further noting that “[c]ountless such machines exist in nature.”5 Indeed, a single research project in 2006 reported the discovery of over 250 new molecular machines in yeast alone!6

Molecular machines have posed a stark challenge to those who seek to understand them in Darwinian terms as the products of an undirected process. In his 1996 book Darwin’s Black Box: The Biochemical Challenge to Evolution, biochemist Michael Behe explained the surprising discovery that life is based upon machines:

Shortly after 1950 science advanced to the point where it could determine the shapes and properties of a few of the molecules that make up living organisms. Slowly, painstakingly, the structures of more and more biological molecules were elucidated, and the way they work inferred from countless experiments. The cumulative results show with piercing clarity that life is based on machines--machines made of molecules! Molecular machines haul cargo from one place in the cell to another along "highways" made of other molecules, while still others act as cables, ropes, and pulleys to hold the cell in shape. Machines turn cellular switches on and off, sometimes killing the cell or causing it to grow. Solar-powered machines capture the energy of photons and store it in chemicals. Electrical machines allow current to flow through nerves. Manufacturing machines build other molecular machines, as well as themselves. Cells swim using machines, copy themselves with machinery, ingest food with machinery. In short, highly sophisticated molecular machines control every cellular process. Thus, the details of life are finely calibrated and the machinery of life enormously complex.7

Behe then posed the question, “Can all of life be fit into Darwin’s theory of evolution?,” and answered: "The complexity of life's foundation has paralyzed science's attempt to account for it; molecular machines raise an as-yet impenetrable barrier to Darwinism's universal reach."8

Even those who disagree with Behe’s answer to that question have marveled at the complexity of molecular machines. In 1998, former president of the U.S. National Academy of Sciences Bruce Alberts wrote the introductory article to an issue of Cell, one of the world’s top biology journals, celebrating molecular machines. Alberts praised the “speed,” “elegance,” “sophistication,” and “highly organized activity” of “remarkable” and “marvelous” structures inside the cell. He went on to explain what inspired such words:

The entire cell can be viewed as a factory that contains an elaborate network of interlocking assembly lines, each of which is composed of a set of large protein machines. . . . Why do we call the large protein assemblies that underlie cell function protein machines? Precisely because, like machines invented by humans to deal efficiently with the macroscopic world, these protein assemblies contain highly coordinated moving parts.9

Likewise, in 2000 Marco Piccolini wrote in Nature Reviews Molecular Cell Biology that “extraordinary biological machines realize the dream of the seventeenth- century scientists … that ‘machines will be eventually found not only unknown to us but also unimaginable by our mind.’” He notes that modern biological machines “surpass the expectations of the early life scientists.”10

A few years later, a review article in the journal Biological Chemistry demonstrated the difficulty evolutionary scientists have faced when trying to understand molecular machines. Essentially, they must deny their scientific intuitions when trying to grapple with the complexity of the fact that biological structures appear engineered to the schematics of blueprints:

Molecular machines, although it may often seem so, are not made with a blueprint at hand. Yet, biochemists and molecular biologists (and many scientists of other disciplines) are used to thinking as an engineer, more precisely a reverse engineer. But there are no blueprints … ‘Nothing in biology makes sense except in the light of evolution’: we know that Dobzhansky (1973) must be right. But our mind, despite being a product of tinkering itself strangely wants us to think like engineers.11

But do molecular machines make sense in the light of undirected Darwinian evolution? Does it make sense to deny the fact that machines show all signs that they were designed? Michael Behe argues that in fact molecular machines meet the very test that Darwin posed to falsify his theory, and indicate intelligent design.

Darwin knew his theory of gradual evolution by natural selection carried a heavy burden:

If it could be demonstrated that any complex organ existed which could not possibly have been formed by numerous, successive, slight modifications, my theory would absolutely break down.

… What type of biological system could not be formed by “numerous successive slight modifications”? Well, for starters, a system that is irreducibly complex. By irreducibly complex I mean a single system which is composed of several interacting parts that contribute to the basic function, and where the removal of any one of the parts causes the system to effectively cease functioning.12

Molecular machines are highly complex and in many cases we are just beginning to understand their inner workings. As a result, while we know that many complex molecular machines exist, to date only a few have been studied sufficiently by biologists so that they have directly tested for irreducible complexity through genetic knockout experiments or mutational sensitivity tests. What follows is a non-exhaustive list briefly describing 40 molecular machines identified in the scientific literature. The first section will cover molecular machines that scientists have argued show irreducible complexity. The second section will discuss molecular machines that may be irreducibly complex, but have not been studied in enough detail yet by biochemists to make a conclusive argument.

Selected list of molecular machines:

I. Molecular Machines that Scientists Have Argued Show Irreducible Complexity

1. Bacterial Flagellum: The flagellum is a rotary motor in bacteria that drives a propeller to spin, much like an outboard motor, powered by ion flow to drive rotary motion. Capable of spinning up to 100,000 rpm,13 one paper in Trends in Microbiology called the flagellum “an exquisitely engineered chemi-osmotic nanomachine; nature’s most powerful rotary motor, harnessing a transmembrane ion-motive force to drive a filamentous propeller.”14 Due to its motor-like structure and internal parts, one molecular biologist wrote in the journal Cell, “[m]ore so than other motors, the flagellum resembles a machine designed by a human.”15 Genetic knockout experiments have shown that the E. coli flagellum is irreducibly complex with respect to its approximately 35 genes.16 Despite the fact that this is one of the best studied molecular machines, a 2006 review article in Nature Reviews Microbiology admitted that “the flagellar research community has scarcely begun to consider how these systems have evolved.”17

2. Eukaryotic Cilium: The cilium is a hair-like, or whip-like structure that is built upon a system of microtubules, typically with nine outer microtubule pairs and two inner microtubules. The microtubules are connected with nexin arms and a paddling-like motion is instigated with dynein motors.18 These machines perform many functions in Eukaryotes, such as allowing sperm to swim or removing foreign particles from the throat. Michael Behe observes that the “paddling” function of the cilium will fail if it is missing any microtubules, connecting arms, or lacks sufficient dynein motors, making it irreducibly complex.19

3. Aminoacyl-tRNA Synthetases (aaRS): aaRS enzymes are responsible for charging tRNAs with the proper amino acid so they can accurately participate in the process of translation. In this function, aaRSs are an “aminoacylation machine.”20 Most cells require twenty different aaRS enzymes, one for each amino acid, without which the transcription/translation machinery could not function properly.21 As one article in Cell Biology International stated: “The nucleotide sequence is also meaningless without a conceptual translative scheme and physical ‘hardware’ capabilities. Ribosomes, tRNAs, aminoacyl tRNA synthetases, and amino acids are all hardware components of the Shannon message ‘receiver’. But the instructions for this machinery is itself coded in DNA and executed by protein ‘workers’ produced by that machinery. Without the machinery and protein workers, the message cannot be received and understood. And without genetic instruction, the machinery cannot be assembled.”22 Arguably, these components form an irreducibly complex system.23

4. Blood clotting cascade: The blood coagulation system “is a typical example of a molecular machine, where the assembly of substrates, enzymes, protein cofactors and calcium ions on a phospholipid surface markedly accelerates the rate of coagulation.”24 According to a paper in BioEssays, “the molecules interact with cell surface (molecules) and other proteins to assemble reaction complexes that can act as a molecular machine.”25 Michael Behe argues, based upon experimental data, that the blood clotting cascade has an irreducible core with respect to its components after its initiation pathways converge.26

5. Ribosome: The ribosome is an “RNA machine”27 that “involves more than 300 proteins and RNAs”28 to form a complex where messenger RNA is translated into protein, thereby playing a crucial role in protein synthesis in the cell. Craig Venter, a leader in genomics and the Human Genome Project, has called the ribosome “an incredibly beautiful complex entity” which requires a “minimum for the ribosome about 53 proteins and 3 polynucleotides,” leading some evolutionist biologists to fear that it may be irreducibly complex.29

6. Antibodies and the Adaptive Immune System: Antibodies are “the ‘fingers’ of the blind immune system—they allow it to distinguish a foreign invader from the body itself.”30 But the processes that generate antibodies require a suite of molecular machines.31 Lymphocyte cells in the blood produce antibodies by mixing and match portions of special genes to produce over 100,000,000 varieties of antibodies.32 This “adaptive immune system” allows the body to tag and destroy most invaders. Michael Behe argues that this system is irreducibly complex because many components must be present for it to function: “A large repertoire of antibodies won’t do much good if there is no system to kill invaders. A system to kill invaders won’t do much good if there’s no way to identify them. At each step we are stopped not only by local system problems, but also by requirements of the integrated system.”33

II. Additional Molecular Machines

7. Spliceosome: The spliceosome removes introns from RNA transcripts prior to translation. According to a paper in Cell, “In order to provide both accuracy to the recognition of reactive splice sites in the pre-mRNA and flexibility to the choice of splice sites during alternative splicing, the spliceosome exhibits exceptional compositional and structural dynamics that are exploited during substrate-dependent complex assembly, catalytic activation, and active site remodeling.”34 A 2009 paper in PNAS observed that “[t]he spliceosome is a massive assembly of 5 RNAs and many proteins”35—another paper suggests “300 distinct proteins and five RNAs, making it among the most complex macromolecular machines known.”36

8. F0F1 ATP Synthase: According to cell biologist and molecular machine modeler David Goodsell, “ATP synthase is one of the wonders of the molecular world.”37 This protein-based molecular machine is actually composed of two distinct rotary motors which joined by a stator: As the F0 motor is powered by protons, it turns the F1 motor. This kinetic energy is used like a generator to synthesize adenosine triphosphate (ATP), the primary energy carrying molecule of cells.38

9. Bacteriorhdopsin: Bacteriorhodopsin “is a compact molecular machine” uses that sunlight energy to pump protons across a membrane.39 Embedded in the cell membrane, it consists of seven helical structures that span the membrane. It also contains retinal, a molecule which changes shape after absorbing light. Photons captured by retinal are forced through the seven helices to the outside of the membrane.40 When protons flow back through the membrane, ATP is formed.

10. Myosin: Myosin is a molecular motor that moves along a “track”—in this case actin filaments—to form the basis of muscle movement or to transport cargoes within the cell.41 Muscles use molecular machines like myosin to “convert chemical energy into mechanical energy during muscle contraction.”42 In fact, muscle movement requires the “combined action of trillions of myosin motors.”43

11. Kinesin Motor: Much like myosin, kinesin is a protein machine that binds to and carries cargoes by “crawls hand-over-hand along a microtubule” in the cell.44 Kinesins are powerful enough to drag large cellular organelles through the cell as well as vesicles or aid in assembly of bipolar spindles, or depolymerization of microtubules.45

12. Tim/Tom Systems: Tim or Tom systems are selective protein pump machines that import proteins across the inner (Tim) and outer (Tom) membranes of mitochondria into the interior matrix of the mitochondria.46

13. Calcium Pump: The calcium pump is an “amazing machine with several moving parts“ that transfers calcium ions across the cell membrane. It is a machine that uses a 4-step cycle during the pump process.47

14. Cytochrome C Oxidase: Cytochrome C Oxidase qualifies as a molecular machine “since part of the redox free energy is transduced into a proton electrochemical gradient.”48 The enzyme’s function is to carefully control the final steps of food oxidation by combining electrons with oxygen and hydrogen to form water, thereby releasing energy. It uses copper and iron atoms to aid in this process.49

15. Proteosome: The proteosome is a large molecular machine whose parts must be must be carefully assembled in a particular order. For example, the 26S proteosome has 33 distinct subunits which enable it to perform its function to degrade and destroy proteins that have been misfolded in the cell or otherwise tagged for destruction.50 One paper suggested that a particular eukaryotic proteasome “is the core complex of an energy-dependent protein degradation machinery that equals the protein synthesis machinery in its complexity.”51

16. Cohesin: Cohesin is molecular machine “multisubunit protein complex"52 and “a macromolecular complex that links sister chromatids together at the metaphase plate during mitosis.”53

17. Condensin: Condensin is a molecular machine that helps to condense and package chromosomes for cell replication. It is a five subunit complex, and is “the key molecular machine of chromosome condensation.”54

18. ClpX: ClpX is a molecular machine that uses ATP to both unfold proteins and then transport unfolded proteins into another complex in the cell. It moves these proteins into the ClpP complex.55

19. Immunological Synapse: The immunological synapse is a molecular machine that serves as an interface to activate of T cells. Once an immunological synapse is completely formed, T Cells are activated and proliferate, sparking key part of the immune response.56

20. Glideosome: The glideosome is a “macromolecular complex” and an “elaborate machine”57 whose function is to allow protozoa to rely on gliding motility over various substrates.

21. Kex2: Kex2 is a molecular machine that facilitates cell fusion during the mating of yeast; it likely works by degrading cell walls.58

22. Hsp70: Hsp70 is one of many molecular machines that serve as chaperones that not only assist other proteins in reaching a proper functional conformation (i.e. proper folding) but also helping them to be transported to the proper location in the cell.59

23. Hsp60: Hsp60 is another chaperone machine – it is tailored to provide “an enclosed environment for folding proteins which totally protects them as they fold.”60 It is composed of multiple proteins which form a barrel shaped structure with a cap.61 Once an unfolded protein is inside, it can fold properly.

24. Protein Kinase C: Protein Kinase C is a molecular machine that is activated by certain calcium and diacylglycerol signals in the cell. It thus acts as an interpreter of electrical signals, as one paper in Cell wrote: “This decoding mechanism may explain how cPKC isoforms can selectively control different cellular processes by relying on selective patterns of calcium and diacylglycerol signals.”62

25. SecYEG PreProtein Translocation Channel: The SecYE complex is vital to the operation of “translocation machinery” which works to move molecules across membranes in the cell.63

26. Hemoglobin: Molecular machine modeller David Goodsell observes that “Hemoglobin is a remarkable molecular machine that uses motion and small structural changes to regulate its action.”64 Hemoglobin uses iron within its protein structure to carry oxygen from the lungs to the rest of the body through the blood.

27. T4 DNA Packaging Motor: The T4 DNA is one of various packaging motors that are “powerful molecular motors” which emplace viral genomes into capsules called procapsids.65 Once viral genome packaging is complete, “the DNA packaging motor is released and the separately assembled tail is attached to produce the mature infectious viral particle.”66

28. Smc5/Smc6: Smc5/Smc6 is a complex machine that is involved with the structural maintenance of chromosomes with regards to cohesions and condensins,67 and works to remove cohesin from damaged chromosomes prior to chromosomal separation,68 and may also work to repair and untangle DNA.69

29. Cytplasmic Dynein: Cytplasmic dynein is a machine involved with cargo transport and movement cell that functions like a motor with a “power stroke.”70 In particular, it transports nuclei in fungi and neurons in mammalian brains.71

30. Mitotic Spindle Machine: The mitotic spindle is a highly dynamic self-assembling complex molecular machine composed of tubulin, motors, and other molecules which assembles around the chromosomes and segregates them into daughter cells during mitosis.72

31. DNA Polymerase: The DNA polymerase is a multiprotein machine that creates a complementary strand of DNA from a template strand.73 The DNA polymerase is not only the “central component of the DNA replication machinery,”74 but it “plays the central role in the processes of life,”75 since it is responsible for the copying of DNA from generating to generation. During the polymerization process, it remains tethered to the DNA using a protein-based sliding clamp.76 It is extremely accurate, making less than one mistake per billion bases, aided by its ability to proofread and fix mistakes.77

32. RNA Polymerase: Like its DNA polymerase counterpart, the function of the RNA polymerase is to create a messenger RNA strand from a DNA template strand. Called "a huge factory with many moving parts,"78 it is a “directional machine and, indeed, as a molecular motor” where it functions “as a dynamic, fluctuating, molecular motor capable of producing force and torque.”79

33. Kinetochore: The kinetochore is a “proteinaceous structure that assembles on centromeric chromatin and connects the centromere to spindle microtubules.”80 Called a “macromolecular protein machine,”81 it is composed of over 80 protein components;82 it aids in separating chromosomes during cell division.

34. MRX Complex: The MRX complex forms telomere length counting machinery that measures the integrity of telomeres, the structures that protect the ends of eukaryotic chromosomes. Properly measuring telomere length is vital to ensure proper cell lifetime and genome stability.83 Yeast use the MRX complex via a “’protein-counting’ mechanism whereby higher numbers of proteins bound by a longer telomere repeat tract ultimately inhibit telomerase activity at that particular telomere.”84

35. Apoptosome / Caspase: While many molecular machines keep a cell alive, there are even machines that are programmed to cause cell death, or apoptosis. Cell death must be carefully timed so that cells die when they need to be replaced. According to David Goodsell, “Caspases are the executioners of apoptosis,” and they work by destroying specific proteins in the right order so as to “disassemble the cell in an orderly manner.”85 Caspases can be part of a “death machine” called the apoptosome,86 a molecular machine which receives signals indicating cellular stress and then initiates cell death, including activity of caspases.

36. Type III Secretory System: This machine, often called the T3SS, is a toxin injection machine used by predatory bacteria to deliver deadly toxins into other cells.87 It is composed of subunits that are machines, such as the injectisome nanomachine.88

37. Type II Secretion Apparatus: The T2SS is a complex nanomachine that translocates proteins across the outer membrane of a bacterium.89

38. Helicase/Topoisomerase Machine: The helicase and topoisomerase machines work together to properly unwrap or unzip DNA prior to transcription of DNA into mRNA or DNA replication.90 Topoisomerase performs this function by cutting one DNA strand and then holding on to the other while the cut strand unwinds.91

39. RNA degradasome: The RNA degradasome “multiprotein complex involved in the degradation of mRNA”92 or trimming RNAs into their active forms93 in E. coli bacteria. Its large size “would readily qualify [it] as a supramolecular machine dedicated to RNA processing and turnover.”94

40. Photosynthetic system: The processes that plants use to convert light into chemical energy a type of molecular machines.95 For example, photosystem 1 contains over three dozen proteins and many chlorophyll and other molecules which convert light energy into useful energy in the cell. “Antenna” molecules help increase the amount of light aborbed.96 Many complex molecules are necessary for this pathway to function properly.

References Cited

[1.] See Marco Piccolino, “Biological machines: from mills to molecules,” Nature Reviews Molecular Cell Biology, Vol. 1:149-153 (November, 2000).

[2.] Marco Piccolino, “Biological machines: from mills to molecules,” Nature Reviews Molecular Cell Biology, Vol. 1:149-153 (November, 2000).

[3.] Thomas Köcher & Giulio Superti-Furga, "Mass spectrometry-based functional proteomics: from molecular machines to protein networks," Nature Methods, Vol. 4(10):807-815 (October, 2007).

[4.] Tinh-Alfredo V. Khuong, Jose E. Junez, Carlos E. Godinez, and Miguel A. Garcia-Garibay, "Crystalline Molecular Machines: A Quest Toward Solid-State Dynamics and Function," Accounts of Chemical Research, Vol. 39(6):413-422 (2006).

[5.] C. Mavroidis, A. Dubey, and M.L. Yarmush, "Molecular Machines," Annual Review of Biomedical Engineering, Vol. 6:363-395 (2004).

[6.] See "The Closest Look Ever At The Cell's Machines,” (January 24, 2006).

[7.] Michael Behe, Darwin’s Black Box: The Biochemical Challenge to Evolution, pp. 4-5 (Free Press, 1996).

[8.] Michael Behe, Darwin’s Black Box: The Biochemical Challenge to Evolution, p. 5 (Free Press, 1996).

[9.] Bruce Alberts, "The Cell as a Collection of Protein Machines: Preparing the Next Generation of Molecular Biologists," Cell, Vol. 92:291 (February 6, 1998).

[10.] Marco Piccolino, “Biological machines: from mills to molecules,” Nature Reviews Molecular Cell Biology, Vol. 1:149-153 (November, 2000).

[11.] Walter Neupert, "Highlight: Molecular Machines," Biological Chemistry, Vol. 386(Cool:711(August, 2005).

[12.] Michael Behe, Darwin’s Black Box: The Biochemical Challenge to Evolution, p. 39 (Free Press, 1996).

[13.] Seiji Kojima and David F. Blair, “The Bacterial Flagellar Motor: Structure and Function of a Complex Molecular Machine,” International Review of Cytology, Vol. 233:93-134 (2004).

[14.] Mark J. Pallen, Charles W. Penn and Roy R. Chaudhuri, “Bacterial flagellar diversity in the post-genomic era,” Trends in Microbiology, Vol. 13(4):143-149 (April, 2005).

[15.] David J. DeRosier, “The turn of the screw: The bacterial flagellar motor,” Cell, Vol. 93: 17-20 (1998).

[16.] See Transcript of Kitzmiller v. Dover Trial, Afternoon Session (Nov. 3, 2005), pp. 99-108.

[17.] Mark J. Pallen and Nicholas J. Matzke, “From The Origin of Species to the Origin of Bacterial Flagella,” Nature Reviews Microbiology, Vol. 4 (September 5, 2006).

[18.] Daniela Nicastro, J. Richard McIntosh, and Wolfgang Baumeister, "3D structure of eukaryotic flagella in a quiescent state revealed by cryo-electron tomography," Proceedings of the U.S. National Academy of Sciences, Vol. 102:15889-15894 (November 1, 2005).

[19.] Michael Behe, Darwin’s Black Box: The Biochemical Challenge to Evolution, p. 65 (Free Press, 1996).

[20.] M.T. Norcum, C. L. Wolfe, and J.A. Warrington, “Three-dimensional Working Model of the Multienzyme Aminoacyl-tRNA Synthetase Complex Determined by Computational Microscopy,” Microsc Microanal, Vol. 11:164-165 (2005).

[21.] See David Goodsell, “Aminoacyl-tRNA Synthetases,” Molecule of the Month at Protein Data Bank (April, 2001).

[22.] J.T. Trevors and D.L. Abel, "Chance and necessity do not explain the origin of life," Cell Biology International, Vol. 28: 729-739 (2004).

[23.] See Stephen C. Meyer, Signature in the Cell: DNA and the Evidence for Intelligent Design, p. 246-249 (HarperOne, 2009).

[24.] Henri M.H. Spronk, José W.P. Govers-Riemslag, and Hugo ten Cate, “The blood coagulation system as a molecular machine,” BioEssays, Vol. 25:1220-1228 (2003).

[25.] Henri M.H. Spronk, José W.P. Govers-Riemslag, and Hugo ten Cate, “The blood coagulation system as a molecular machine,” BioEssays, Vol. 25:1220-1228 (2003).

[26.] Michael Behe, Darwin’s Black Box: The Biochemical Challenge to Evolution, p 86 (Free Press, 1996).

[27.] Thomas R. Cech, “Crawling Out of the RNA World,” Cell, Vol. 136:599-602 (February 20, 2009).

[28.] Jonathan P Staley and John L Woolford, Jr, “Assembly of ribosomes and spliceosomes: complex ribonucleoprotein machines,” Current Opinion in Cell Biology, Vol. 21(1):109-118 (February, 2009).

[29.] “Life: What A Concept!” (The Edge Foundation, 2008).

[30.] Michael Behe, Darwin’s Black Box: The Biochemical Challenge to Evolution, p. 120 (Free Press, 1996).

[31.] Marco Piccolino, “Biological machines: from mills to molecules,” Nature Reviews Molecular Cell Biology, Vol. 1:149-153 (November, 2000).

[32.] See David Goodsell, “Antibodies,” Molecule of the Month at Protein Data Bank (September, 2001).

[33.] Michael Behe, Darwin’s Black Box: The Biochemical Challenge to Evolution, p. 138 (Free Press, 1996).

[34.] Markus C. Wahl, Cindy L. Will, and Reinhard Lührmann, "The Spliceosome: Design Principles of a Dynamic RNP Machine," Cell, Vol. 136: 701-718 (February 20, 2009).

[35.] Samuel E. Butcher, “The spliceosome as ribozyme hypothesis takes a second step,” Proceedings of the U.S. National Academy of Sciences, Vol. 106(30):12211-12212 (July 28, 2009).

[36.] Timothy W. Nilsen, "The spliceosome: the most complex macromolecular machine in the cell?," BioEssays, Vol. 25:1147-1149 (2003).

[37.] See David Goodsell, “The ATP Synthase,” Molecule of the Month at Protein Data Bank (December, 2005).

[38.] C. Mavroidis, A. Dubey, and M.L. Yarmush, "Molecular Machines," Annual Review of Biomedical Engineering, Vol. 6:363-395 (2004); Paul D. Boyer, "The ATP Synthase--A Splendid Molecular Machine," Vol. 66:717-749 (1997); Steven M. Block, "Real engines of creation," Nature, Vol. 386:217-219 (March 20, 1997).

[39.] See David Goodsell, “Bacteriorhodopsin,” Molecule of the Month at Protein Data Bank (March, 2002).

[40.] Werner Kühlbrandt, "Bacteriorhodopsin — the movie," Nature, Vol. 406:569-570 (August 10, 2009).

[41.] C. Mavroidis, A. Dubey, and M.L. Yarmush, "Molecular Machines," Annual Review of Biomedical Engineering, Vol. 6:363-395 (2004); Ronald D. Vale, “The Molecular Motor Toolbox for Intracellular Transport,” Cell, Vol. 112:467-480 (February 21, 2003).

[42.] Marco Piccolino, “Biological machines: from mills to molecules,” Nature Reviews Molecular Cell Biology, Vol. 1:149-153 (November, 2000).

[43.] See David Goodsell, “The Calcium Pump,” Molecule of the Month at Protein Data Bank (March, 2004).

[44.] C. Mavroidis, A. Dubey, and M.L. Yarmush, “Molecular Machines,” Annual Review of Biomedical Engineering, Vol. 6:363-395 (2004); Ronald D. Vale, “The Molecular Motor Toolbox for Intracellular Transport,” Cell, Vol. 112:467-480 (February 21, 2003); David Goodsell, “Kinesin,” Molecule of the Month at Protein Data Bank (April, 2005).

[45.] Sharyn A. Endow, “Kinesin motors as molecular machines,” BioEssays, Vol. 25:1212-1219 (2003).

[46.] Nikolaus Pfanner and Michiel Meijer, “Mitochondrial biogenesis: The Tom and Tim machine,” Current Biology, Vol. 7:R100-R103 (1997).

[47.] See David Goodsell, “The Calcium Pump,” Molecule of the Month at Protein Data Bank (March, 2004).

[48.] Francesco Malatesta, Giovanni Antonini, Paolo Sarti, Maurizio Brunori, "Structure and function of a molecular machine: cytochrome c oxidase," Biophysical Chemistry, Vol. 54: 1-33 (1995).

[49.] See David Goodsell, “Cytochrome c Oxidase,” Molecule of the Month at Protein Data Bank (May, 2000).

[50.] Henrike C. Besche, Andreas Peth, and Alfred L. Goldberg, “Getting to First Base in Proteasome Assembly,” Cell, Vol. 138:25-28 (July 10, 2009).

[51.] Wolfgang Baumeister, Jochen Walz, Frank Zu¨hl, and Erika Seemu¨ller, “The Proteasome: Paradigm of a Self-Compartmentalizing Protease,” Cell, Vol. 92:367-380 (February 6, 1998).

[52.] Jan-Michael Peters, Antonio Tedeschi, and Julia Schmitz, “The cohesin complex and its roles in chromosome biology,” Genes & Development, Vol. 22:3089-3114 (2008).

[53.] Susan Jones and John Sgouros, “The cohesin complex: sequence homologies, interaction networks and shared motifs,” Genome Biology, Vol 2(3) (March 6, 2001); John Mc Intyre, Eric GD Muller, Stefan Weitzer, Brian E Snydsman, Trisha N Davis, and Frank Uhlmann, “In vivo analysis of cohesin architecture using FRET in the budding yeast Saccharomyces cerevisiae,” The EMBO Journal, Vol. 26, 3783-3793 (2007).

[54.] Alexander V. Strunnikov, "Condensin and biological role of chromosome condensation," Progress in Cell Cycle Research, Vol. 5:361-367, (2003).

[55.] Steven E. Glynn, Andreas Martin, Andrew R. Nager, Tania A. Baker, and Robert T. Sauer, “Structures of Asymmetric ClpX Hexamers Reveal Nucleotide-Dependent Motions in a AAA+ Protein-Unfolding Machine,” Cell, Vol. 139:744-756 (November 13, 2009).

[56.] Arash Grakoui, Shannon K. Bromley, Cenk Sumen, Mark M. Davis, Andrey S. Shaw, Paul M. Allen, Michael L. Dustin, “The Immunological Synapse: A Molecular Machine Controlling T Cell Activation,” Science, Vol. 285:221-227 (July 9, 1999).

[57.] Anthony Keeley and Dominique Soldati, ”The glideosome: a molecular machine powering motility and host-cell invasion by Apicomplexa,” Trends in Cell Biology, Vol.14(10): 528-532 (October, 2004).

[58.] Maxwell G. Heiman, Alex Engel, and Peter Walter, "The Golgi-resident protease Kex2 acts in conjunction with Prm1 to facilitate cell fusion during yeast mating," The Journal of Cell Biology, Vol. 176:209-222 (January 15, 2007).

[59.] Bernd Bukau and Arthur L. Horwich, “The Hsp70 and Hsp60 Chaperone Machines,” Cell, Vol. 92: 351-366 (February 6, 1998).

[60.] See David Goodsell, “Chaperones,” Molecule of the Month at Protein Data Bank (August, 2002).

[61.] “The Birth, Assembly, and Death of Proteins,” Molecular Biology of the Cell at NCBI.

[62.] Elena Oancea and Tobias Meyer, “Protein Kinase C as a Molecular Machine for Decoding Calcium and Diacylglycerol Signals,” Cell, Vol. 95:307–318 (October 30, 1998).

[63.] Pascal Bessonneau, Veronique Besson, Ian Collinson, and Franck Duong, “The SecYEG preprotein translocation channel is a conformationally dynamic and dimeric structure,” The EMBO Journal, Vol. 21(5): 995-1003 (2002).

[64.] See David Goodsell, “Hemoglobin,” Molecule of the Month at Protein Data Bank (May, 2003).

[65.] Siyang Sun, Kiran Kondabagil, Bonnie Draper, Tanfis I. Alam, Valorie D. Bowman, Zhihong Zhang, Shylaja Hegde, Andrei Fokine, Michael G. Rossmann, and Venigalla B. Rao, “The Structure of the Phage T4 DNA Packaging Motor Suggests a Mechanism Dependent on Electrostatic Forces,” Cell, Vol. 135:1251-1262 (December 26, 2008).

[66.] Siyang Sun, Kiran Kondabagil, Bonnie Draper, Tanfis I. Alam, Valorie D. Bowman, Zhihong Zhang, Shylaja Hegde, Andrei Fokine, Michael G. Rossmann, and Venigalla B. Rao, “The Structure of the Phage T4 DNA Packaging Motor Suggests a Mechanism Dependent on Electrostatic Forces,” Cell, Vol. 135:1251-1262 (December 26, 2008).

[67.] Jordi Torres-Rosell, Ivana Sunjevaric, Giacomo De Piccoli, Meik Sacher, Nadine Eckert-Boulet, Robert Reid, Stefan Jentsch, Rodney Rothstein, Luis Aragón, and Michael Lisby, “The Smc5–Smc6 complex and SUMO modification of Rad52 regulates recombinational repair at the ribosomal gene locus,” Nature Cell Biology, Vol. 9(Cool:923-931 (August, 2007).

[68.] Emily A. Outwin, Anja Irmisch, Johanne M. Murray, and Matthew J. O’Connell, “Smc5-Smc6-Dependent Removal of Cohesin from Mitotic Chromosomes,” Molecular and Cell Biology, Vol. 29 (16): 4363–4375 (August 2009).

[69.] “A Protein Complex That Untangles DNA,” (July 16, 2006).

[70.] C. Mavroidis, A. Dubey, and M.L. Yarmush, “Molecular Machines,” Annual Review of Biomedical Engineering, Vol. 6:363-395 (2004).

[71.] Ronald D. Vale, “The Molecular Motor Toolbox for Intracellular Transport,” Cell, Vol. 112:467-480 (February 21, 2003).

[72.] E. Karsenti and I. Vernos, "The Mitotic Spindle: A Self-Made Machine," Science, Vol. 294:543-547 (October 19, 2001); Raja Paul, Roy Wollman, William T. Silkworth, Isaac K. Nardi, Daniela Cimini, and Alex Mogilner, "Computer simulations predict that chromosome movements and rotations accelerate mitotic spindle assembly without compromising accuracy," Proceedings of the U.S. National Academy of Sciences, Vol. 106(37):15708-15713 (September 15, 2009).

[73.] Jennifer Turner, Manju M. Hingorani, Zvi Kelman, and Mike O’Donnell, "The internal workings of a DNA polymerase clamp-loading machine," The EMBO Journal, Vol.18:771-783 (1999); “DNA Polymerase: an Active Machine,” The Journal of Biological Chemistry, Vol. 282:e99940 (September 28, 2007).

[74.] Paul J. Rothwell and Gabriel Waksman, "A Pre-equilibrium before Nucleotide Binding Limits Fingers Subdomain Closure by Klentaq1," The Journal of Biological Chemistry, Vol. 282(39):28884-28892 (September 28, 2007).

[75.] See David Goodsell, “DNA Polymerase,” Molecule of the Month at Protein Data Bank (March, 2000).

[76.] Jennifer Turner, Manju M. Hingorani, Zvi Kelman, and Mike O’Donnell, "The internal workings of a DNA polymerase clamp-loading machine," The EMBO Journal, Vol.18:771-783 (1999).

[77.] See David Goodsell, “DNA Polymerase,” Molecule of the Month at Protein Data Bank (March, 2000).

[78.] See David Goodsell, “RNA Polymerase,” Molecule of the Month at Protein Data Bank (April, 2003).

[79.] Henri Buc and Terence Strick, RNA polymerases as molecular motors , p. 304 (Royal Society of Chemistry, 2009).

[80.] Steven Henikoff, Kami Ahmad, Harmit S. Malik, “The Centromere Paradox: Stable Inheritance with Rapidly Evolving DNA,” Science, Vol. 293:1098-1102 (August 10, 2001).

[81.] Ajit Joglekar, Kerry Bloom, and E. D. Salmon, "In vivo protein architecture of the eukaryotic kinetochore with nanometer scale accuracy," Current Biology, Vol. 19(Cool:694-699 (April 28, 2009).

[82.] Iain M. Cheeseman & Arshad Desai, “Molecular architecture of the kinetochore-microtubule interface,” Nature Reviews Molecular Cell Biology, Vol. 9:33-46 (2008).

[83.] Neal F. Lue, “Closing the Feedback Loop: How Cells ‘Count’ Telomere-Bound Proteins,” Molecular Cell, Vol. 33:413-414 (February 27, 2009).

[84.] Neal F. Lue, “Closing the Feedback Loop: How Cells ‘Count’ Telomere-Bound Proteins,” Molecular Cell, Vol. 33:413-414 (February 27, 2009).

[85.] See David Goodsell, “Caspases,” Molecule of the Month at Protein Data Bank (August, 2004).

[86.] Guy S. Salvesen and Martin Renatus, “Apoptosome: The Seven-Spoked Death Machine,” Developmental Cell, Vol. 2(3): 256-257 (March 1, 2002).

[87.] Jorge E. Galán and Alan Collmer, “Type III Secretion Machines: Bacterial Devices for Protein Delivery into Host Cells,” Science, Vol. 284:1322-1328 (May 21, 1999).

[88.] Guy R. Cornelis, "The type III secretion injectisome," Nature Reviews Microbiology, Vol. 4:811-825 (November, 2006).

[89.] Guy R. Cornelis, "The type III secretion injectisome," Nature Reviews Microbiology, Vol. 4:811-825 (November, 2006).

[90.] Michel Duguet, "When helicase and topoisomerase meet!," Journal of Cell Science, Vol. 110:1345-1350 (1997).

[91.] See David Goodsell, “Topoisomerases,” Molecule of the Month at Protein Data Bank (January, 2006).

[92.] Agamemnon J. Carpousis, “The RNA Degradosome of Escherichia coli: An mRNA-Degrading Machine Assembled on RNase E,” Annual Review of Microbiology, Vol. 61:71-87 (October 2007).

[93.] Maria Jose Marcaida, Mark A. DePristo, Vidya Chandran, Agamemnon J. Carpousis and Ben F. Luisi, “The RNA degradosome: life in the fast lane of adaptive molecular evolution,” Trends in Biochemical Sciences, Vol. 31(7): 359-3365 (July 2006).

[94.] Maria Jose Marcaida, Mark A. DePristo, Vidya Chandran, Agamemnon J. Carpousis and Ben F. Luisi, “The RNA degradosome: life in the fast lane of adaptive molecular evolution,” Trends in Biochemical Sciences, Vol. 31(7): 359-3365 (July 2006).

[95.] Marco Piccolino, “Biological machines: from mills to molecules,” Nature Reviews Molecular Cell Biology, Vol. 1:149-153 (November, 2000).

[96.] See David Goodsell, “Photosystem I,” Molecule of the Month at Protein Data Bank (October, 2001).

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3 Re: Molecular machines in biology on Tue Aug 04, 2015 7:58 pm


Molecular machines cannot perform their functions until many parts are present and coordinated, they cannot be built by the "numerous, successive, slight modifications" required by Darwinian evolution. As Behe notes, "The complexity of life's foundation has paralyzed science's attempt to account for it; molecular machines raise an as-yet impenetrable barrier to Darwinism's universal reach."

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4 More Cell Machines Come to Light on Fri Sep 25, 2015 11:27 am


More Cell Machines Come to Light 1

The living cell contains thousands of molecular machines converting energy into useful work. Here are just a few that were recently described in journal papers.
Any given week in the Proceedings of the National Academy of Sciences (PNAS), one is likely to find at least a dozen papers about molecular machines in the cell. Papers about biochemistry usually outnumber those in any other field of science. As imaging techniques continue to improve, the study of cellular machines has thrived, giving scientists better looks at the workings of the cell at higher magnification and finer resolution. This trend shows no sign of stopping.
Those who have seen the film Unlocking the Mystery of Life remember the bacterial flagellum—an outboard motor. They may also remember Jed Macosko saying that a cell has “thousands of machines.” Some of the better-known ones, like the rotary engine ATP synthase and the tightrope-walking dynein, may also be familiar. Let’s take a look at samples from this last week’s catalog of machines discussed in one journal, PNAS, to get a taste of the variety of equipment keeping every cell in operation.

The peroxide sensor (PNAS): Hydrogen peroxide, a powerful oxidant, can damage cells. Some types of bacteria have a special machine, OxyR, with four large domains, that sense H2O2 molecules. When a peroxide molecule is captured, one domain of the machine undergoes a “large conformational change” that triggers the regulatory domains into action.

Peroxisome splitter (PNAS): Peroxides, along other reactive oxygen species and long-chain fatty acids are disposed of in a molecular furnace called the peroxisome. This organelle, containing enzymes involved in many metabolic processes, is duplicated by fission, similar to cell division. A molecular scissors named Peroxin 11 is responsible for initiation of the process; the researchers discovered that it is also important for the final step, scission, producing the two daughter organelles. Interestingly, this machine is “conserved” [unevolved] from yeast to mammalians.”

The shape shifter (PNAS): These authors introduce their machine by saying, “Cells constantly sense and respond to mechanical signals by reorganizing their actin cytoskeleton.” They describe how a force applied to the cell membrane triggers a burst of calcium ions that, in turn, triggers actin molecules around the nucleus to reorganize the skeleton. The actin filaments form a “perinuclear rim” that “may function as a kinetic barrier to protect genome integrity until cellular homeostasis is reestablished.”

The volume control (PNAS): This machine is right in the back of your eyeballs. Retina pigment cells must control their volume; how do they do it? There’s a volume-activated anion channel (VRAC) able to respond to swelling by opening its gates to let out excess ions. When this machine breaks because of mutations, macular dystrophy can result.

Powerstroke of the walker (PNAS): This paper says, “Kinesin molecular motors couple ATP turnover to force production to generate microtubule-based movement and microtubule dynamics.” The authors discuss kinesin-14 from fruit flies, and show how its conversion of ATP to motion during the powerstroke is more complicated than thought. Then they say, “These findings are significant because they reveal that the key principles for force generation by kinesin-14s are conserved [i.e., unevolved] from yeast to higher eukaryotes.”

The thermostat (PNAS): A machine call DesK responds to temperature changes (“essential to cell survival”) by triggering a reversible “zipper” mechanism. In bacterial cells, the transmembrane machine switches its shape if the temperature rises on the outside, triggering additional motions on the inside that can switch on other machines that induce other molecular responses. “The reversible formation of a serine zipper represents a novel mechanism by which membrane-embedded sensors may detect and transmit signals.”

The tightrope walker (PNAS): The two-legged robot dynein walks on tightropes of microtubules, carrying cargo around the cell. Its feet (actually called “heads” by biochemists) have to be able to attach to the microtubules, but can switch from one rope to another as they move. This team investigated what happens when tension is applied to the machine. They dynein will slide if applied in one direction, but fasten more firmly in the other direction. This response is regulated by four additional machines (AAA1-4) that each use ATP as well.

The emergency squad (PNAS): One of the worst emergencies in a cell is when both strands of a DNA double helix snap; it can trigger death of the cell or serious malfunction, leading to disease or cancer. Cosmic rays, chemicals or failures in normal cell processes like transcription can cause double-stranded breaks. Fortunately, there’s an emergency response team named NHEJ (non-homologous end-joining) that knows what to do. The researchers used super-resolution microscopy to watch the team build long filaments at either side of the break as one step in the repair process.
A machine is a device that converts energy into work—not just any work, but directed, useful, functional work. The authors of these and many other papers have no hesitation calling these proteins “machines” and “motors.” Scientists have known about enzymes and proteins for well over a century, but understanding that cells operate with actual machines only dates back about 20 years or so. This revelation—that life operates by thousands of tiny mechanical devices—surely deserves to be called one of the most astounding discoveries in the history of science.

One might compare this discovery to zooming in on what happens when a building is built. Perhaps you’ve watched one of those time-lapse films of a construction project. From a distance, you see just the major features taking shape. If you had never seen such a process before, you might assume this is “just what happens” from time to time. Then, as you are given a series of telescopes with higher and higher resolution, with the ability to stop individual frames of the sequence, the true picture becomes increasingly clear. You find hundreds of people down there operating cranes, bulldozers, ropes, pulleys, ramps and trucks. As you zoom in closer, you see them working in squads, communicating with phones, shaking hands, pointing and responding to each other’s actions. Undoubtedly, your appreciation of what’s involved in construction of a building would grow dramatically.
Now shrink that down a billion-fold. Since the first humans opened their eyes and beheld the living world, there was plenty to show design. But we were like the viewer of the construction project from miles away, unaware of the actual way things work. People understood their bodies and the actions of animals or growth of plants at a macro level only: the running of a deer through a forest, the joy of eating good food and the necessity of disposing of waste, the act of sex and the birth of a child. When layers inside the body became exposed on the hunt, or through injury, a little more of the complexity would be apparent. But without detailed knowledge of what makes a heart beat, or what a liver or kidney actually does, these still might be taken for granted. Except for occasional insights from classical scholars like Aristotle, Hippocrates and Galen, the history of modern medicine and physiology only goes back a few centuries out of the thousands of years man has existed. Modern science starting the zoom-in view on the construction view. Leeuwenhoek opened the world’s eyes to the microbial world; he was astonished to see some of them dancing about with elegant motions.
Fast-forward to about 1995 to the present. We are privileged to live in an age of unprecedented discovery, where our view has zoomed in to the range of billionths of a meter. What did we find? Just fluids jostling about, undergoing chemical reactions? No! A thousand times no! We found machines at work in factories, interacting with incredible efficiency. We found libraries of digital code. We found machines reading the code, translating it, and converting it into other machines. We found thermostats, walking robots, rotary engines, emergency response squads, and long-distance communication networks. We found temperature sensors, volume sensors, disposal services, packaging services, and defense systems. Sex was no longer the transfer of a featureless fluid from the male to the female, but a process of unbelievable complexity involving swimming robots carrying gigabytes of information to be joined to a very complex egg cell with more gigabytes of information, triggering a cascade of machines building machines all the way to a complete baby. The growth of a seedling into a plant is no longer to be shrugged off as something that happens from time to time in nature, but a complex interplay of hormones triggering changes to thousands of molecular machines in plant cells. It’s a planet of machinery! Look around and consider how every living organism, from the worm in the soil, to the bee pollinating a flower, to the hummingbird in the garden, to the tree growing higher and higher in your back yard, operates through the action of thousands of molecular machines that we have begun to understand only in the last tenth of 1% of recorded human history.
If the wonder of what we have discovered doesn’t make you shout “Praise the Lord!” as never before, you might be asleep or dead.
Tragically, praise has been the last thing on the minds of many scientists studying these things. A century and a half of Darwinian dogma has blinded their minds to the obvious inference to intelligent design from molecular machines. We find, however, some curious things in these papers. One is the frequent use of “remarkable” by the authors when they uncover something wonderful. Another is the increasing silence about Darwinism as more details come to light. (There’s an inverse relationship between the frequency of evolution-words to the amount of detail in scientific papers about molecular machines.) A third curious thing is biomimetics: i.e., how cellular machines inspire thoughts of copying those designs for human applications. Together, these curiosities in PNAS and other journals hint that the consciences of evolutionary biologists are not completely dead. A flicker of the design inference still burns and may catch fire some day. When it does, it could burn away the Darwinian chaff, liberate philosophy to once again celebrate natural design as real and pervasive, and provide rational grounds for people of understanding in academia to shout unrestrained, “Great is the Lord, and greatly to be praised!”


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5 Re: Molecular machines in biology on Tue Dec 01, 2015 2:58 pm



Making molecular machines work


Some biological molecular machines

The most complex molecular machines are proteins found within cells. These include motor proteins, such as myosin, which is responsible for muscle contraction, kinesin, which moves cargo inside cells away from the nucleusalong microtubules, and dynein, which produces the axonemal beating of motile cilia and flagella. These proteins and their nanoscale dynamics are far more complex than any molecular machines that have yet been artificially constructed.
Probably the most significant biological machine known is the ribosome. Other important examples include ciliary mobility. A high-level-abstraction summary is that, "[i]n effect, the [motile cilium] is a nanomachine composed of perhaps over 600 proteins in molecular complexes, many of which also function independently as nanomachines."[1] Flexible linker domains allow the connecting protein domains to recruit their binding partners and induce long-range allostery via protein domain dynamics. [5]
This protein flexibility allows the construction of biological machines. The first useful applications of these biological machines might be in nanomedicine. For example,[6] they could be used to identify and destroy cancer cells.[7][8]Molecular nanotechnology is a speculative subfield of nanotechnology regarding the possibility of engineering molecular assemblers, biological machines which could re-order matter at a molecular or atomic scale. Nanomedicine would make use of these nanorobots, introduced into the body, to repair or detect damages and infections. Molecular nanotechnology is highly theoretical, seeking to anticipate what inventions nanotechnology might yield and to propose an agenda for future inquiry. The proposed elements of molecular nanotechnology, such as molecular assemblers and nanorobots are far beyond current capabilities.[9][10]

Molecular Machines

Putting the Pieces Together

 It is now clear that most functions in the cell are not carried out by single protein enzymes, colliding randomly within the cellular jungle, but by macromolecular complexes containing multiple subunits with specific functions (Alberts 1998). Many of these complexes are described as “molecular machines.” Indeed, this designation captures many of the aspects characterizing these biological complexes: modularity, complexity, cyclic function, and, in most cases, the consumption of energy. Examples of such molecular machines are the replisome, the transcriptional machinery, the spliceosome, and the ribosome.

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Molecular Machines Use Physics to Do Mechanical Work 1

One of the channels in the cell membrane that opens to let ions in turns out to act like a molecular spring. includes an animated diagram of NOMPC (“nomp-see”) that works in a fly’s sense of touch and hearing. The channel is made up of four units that each appear to respond to mechanical pressure much like a spring. Researchers from the University of California, publishing their findings in Nature, believe that as the spring is compressed, the channel opens to let the ions flow. This would make sense, because to respond to touch, channels must be directly pulled or twisted open by microscopic forces somehow, but more work will be needed to actually witness the physics in action.

Mechanotransduction 6
Mechanotransduction is the process of converting physical forces into intracellular biochemical responses. The rebirth/change in view toward tissue engineering has made "mechanotransduction" a major buzzword in the field. Essentially, this term generally refers to the mechanical factors that influence cell behavior and differentiation. Stretch, substrate stiffness, loading (compressive, tensile, shear): these are all mechanical loads that are 'sensed' or felt by a cell and are converted into biochemical response such as up or down regulated expression of proteins, cell movement, and/or cell spreading. Ion channels, integrins which are connected to the cytoskeleton, growth factor receptors, cytoskeletal filaments, and even the nucleus of a cell are thought to be 'mechanically activated' and respond directly to, say, stretch of a cell. While exact pathways of converting mechanical stimulus into biochemical response varies among cell types (and even within a cell type) it has become clear that cells have a strong sense of their mechanical environment and respond to changes in this environment.

Electron cryo-microscopy structure of the mechanotransduction channel NOMPC 3
Mechanosensory transduction for senses such as proprioception, touch, balance, acceleration, hearing and pain relies on mechanotransduction channels, which convert mechanical stimuli into electrical signals in specialized sensory cells. How force gates mechanotransduction channels is a central question in the field, for which there are two major models. One is the membrane-tension model: force applied to the membrane generates a change in membrane tension that is sufficient to gate the channel, as in the bacterial MscL channel and certain eukaryotic potassium channels. The other is the tether model: force is transmitted via a tether to gate the channel. The transient receptor potential (TRP) channel NOMPC is important for mechanosensation-related behaviors such as locomotion, touch and sound sensation across different species including Caenorhabditis elegans, Drosophila and zebrafish. NOMPC is the founding member of the TRPN subfamily and is thought to be gated by tethering of its ankyrin repeat domain to microtubules of the cytoskeleton. Thus, a goal of studying NOMPC is to reveal the underlying mechanism of forceinduced gating, which could serve as a paradigm of the tether model. NOMPC fulfils all the criteria that apply to mechanotransduction channels and has 29 ankyrin repeats, the largest number among TRP channels. A key question is how the long ankyrin repeat domain is organized as a tether that can trigger channel gating. Here we present a de novo atomic structure of Drosophila NOMPC determined by single-particle electron cryo-microscopy. Structural analysis suggests that the ankyrin repeat domain of NOMPC resembles a helical spring, suggesting its role of linking mechanical displacement of the cytoskeleton to the opening of the channel. The NOMPC architecture underscores the basis of translating mechanical force into an electrical signal within a cell.

Molecular springs produce a fly's sense of touch and hearing 3

As senses go, there's nothing so immediate and concrete as our sense of touch. So it may come as a surprise that, on the molecular level, our sense of touch is still poorly understood.

Each of our senses relies on "receptor" molecules that turn signals like light, sound, and movement into electrical impulses for nerves to carry to the brain. Scientists have a fairly complete understanding of how receptors in the eye translate light into sight, and they've mapped many of the proteins in the nose and mouth that translate chemical signals into smell and taste.
But still mysterious are the "mechanoreceptors," which detect cells' motion to produce our senses of touch and hearing, and even pick up on our body's position and the flow of blood through our veins.
Now, UC San Francisco scientists have mapped in exquisite detail a protein complex called NOMPC (pronounced "nomp-see"), which acts as a mechanoreceptor in animals from fruit flies to fish and frogs. The structure, reported June 26, 2017 in Nature, reveals a machine that depends on a quartet of tiny springs that tether the complex to the cell's "skeleton" and react to its movement.
Though NOMPC is not found in mammals like us, the new structure gives scientists a better understanding of the subtle machinery that may allow our own sensory cells to detect touch.

In particular, the channels responsible for the human sense of hearing – which works by picking up subtle vibrations in the air – have thus far evaded detailed study. If, as some scientists hypothesize, a tethered receptor is responsible for our sense of hearing, it may well work much like NOMPC.

Springs Could Fine-Tune Channel's Sensitivity
The NOMPC receptor was mapped in such detail thanks to recent technological breakthroughs in a technique known as single particle electron cryo-microscopy.  NOMPC receptor was revealed as a bundle of four identical proteins that sits in a cell's membrane, each with a spring-like tether reaching into the cell.

The  receptor does not respond to movements in the membrane alone, but that larger movements in the cytoskeleton – the network of structural fibers that allow the cell to hold its shape – cause bundle to open up, forming a hole in the cell's membrane. Charged ions rush through the hole into the cell, creating an electrical impulse that signals touch to the nervous system.
Previously mapped touch receptors float free in the cell membrane, responding only when their particular patch of the cell's surface changes shape. But the new structural data show how NOMPC's spring-like tethers might tie it to the cytoskeleton, potentially enabling the receptor to sense distant changes in the cell's shape. Nature has created its own tiny spring to tie the receptor to the cytoskeleton."

Do You Pull It? Push It? Twist It?
To fully understand how channels like NOMPC open and close, scientists must observe the structure of the channels in both open and closed states. This is relatively easy for proteins that respond to light, like those in our retina, or to chemicals, like those in our nose and mouth, since they can be triggered remotely – by a beam of light or a chemical wash, respectively. But the proteins that coordinate the mechanical senses – like touch and hearing – must be directly pulled or twisted open by microscopic forces. This is challenging for scientists to do in a controlled way. "It's difficult to apply a directional force to all these individual molecules," said David Bulkley, a postdoc in the Cheng lab and the other lead author on the study. "And we don't know which direction will activate the channel – do you pull it, do you push it, do you twist it?" To work around this problem, the scientists are looking to find ways to force the channel open – perhaps by finding a molecule that binds to and locks open the protein, or by producing mutant versions of the protein which are stuck in the "open" position. In the meantime, the team is also working to generate computational models of the protein. The high-resolution structure they've obtained will help them simulate in detail what happens when the tethers are put under tension.

Gating prokaryotic mechanosensitive channels 4
Prokaryotic mechanosensitive channels function as molecular switches that transduce bilayer deformations into protein motion. These protein structural rearrangements generate large non-selective pores that function as a prokaryotic ‘last line of defense’ to sudden osmotic challenges. Once considered an electrophysiological artifact, recent structural, spectroscopic and functional data have placed this class of protein at the center of efforts to understand the molecular basis of lipid–protein interactions and their influence on protein function.

Life as a free-living unicellular organism is associated with a vulnerability to radical environmental changes. This life strategy also provides a constant selective pressure that drives the evolution of mechanisms to cope with the numerous inconveniences imposed by nature.

Question: How could the first life-forms have survived without these mechanisms to cope with the changing environmental conditions?  Had these mechanisms not to be fully developed to permit these life forms to adapt to the environment, right from the beginning?

Therefore, much of the prokaryotic genome encodes membrane-protein systems that help to regulate, for example, intracellular pH, the concentrations of all ions and many signaling molecules, the ability to pump toxic substances out of cells, and membrane fluidity in response to temperature changes. Particularly interesting physiological strategies relate to the control of cell volume and the associated responses to osmolarity changes. For a prokaryote, when the surrounding medium becomes hyperosmotic, water leaves the cell, which potentially increases the intracellular ionic strength and therefore affects the electrostatic balance that drives various cellular processes. The effects of hyperosmotic 5 environments are counterbalanced by the existence of transport mechanisms that help to accumulate a few specific osmolites (for example, proline) in cells, and so reduce the movement of water out of the cytoplasm by increasing solute concentrations. When the external environment becomes hypo-osmotic, water enters the cell, which increases membrane turgor and can potentially destroy the cell. This cellular emergency is usually defused by mechanosensitive channels. In response to changes in bilayer tension, these membrane proteins open to form large aqueous pores that allow the passage of both solute and solvent, and quickly equilibrate any hypo-osmotic imbalance4–9 (FIG. 1).

Because of the various modes of gating and the wide range of ionic selectivities, mechanosensitive channels have been classified according to their functional properties, and are therefore considered to be molecularly
heterogeneous. Some of these channels have been identified biochemically and cloned, including certain families of prokaryotic mechanosensitive channels that are found in both archaea and eubacteria. Eukaryotic
mechanosensitive channels have also been identified and cloned, and these belong to the degenerin/epithelial Na+ channel (DEG/ENaC) family and the transient receptor potential (TRP)-channel family (for example,
TRPA1, which was recently identified as the molecular determinant of mechanosensitivity in the cochlea;.

Prokaryotic mechanosensitive channels are gated through changes in bilayer tension (as are members of the eukaryotic two-pore-domain potassium K+channel family), whereas eukaryotic mechanosensitive channels usually respond to mechanical stimuli through their association with cytoskeletal elements. Nevertheless, the recent identification and cloning of the eukaryotic stretch-activated channel TRPC1 (also known as MscCa)17 showed
that bilayer-dependent mechanotransduction might be more common in eukaryotic systems than was previously thought.


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