August 11, 2009 | David F. Coppedge

Protein Function: It’s All in the Fold

Most chemical reactions involve atoms or molecules bumping into one another and exchanging electrons.  Proteins, by contrast, derive their immense functional repertoire from their shapes.  Several recent studies explore the amazing potential for strength, motility and catalysis that derives from the way proteins fold.

  1. Clots:  A picture of fibrin graces an article in Science Daily.  This protein is responsible for blood clotting.  It has a remarkable property of stretching that comes from unfolding as stresses are applied.  “Understanding blood clot mechanics could help in the design of new treatments not only to prevent or remove clots that cause heart attacks and strokes but also to enhance blood clotting in people with bleeding disorders,” the article said. 
  2. Muscle stack:  Titin is an appropriately named protein active in muscle.  Its remarkable ability to maintain strength while stretching comes from the way it folds into stacks of sheet-like material.  A commentary in PNAS by Ronald S. Rock described recent work by Bertz et al that shows how another component, telethonin, sitting like a mattress between sheets of titin, contributes to the function.  “What they found was surprising: not only was this the most robust protein or protein complex ever measured, but it also could withstand nearly half the force required to break a covalent bond.  Clearly, there are some unusual features of this complex that lead to its remarkable stability.”  They also found that the strength was dependent on the direction of the force applied.  This led Rock to ask, “With these key structural features identified, can we now engineer these stabilizing interactions where none existed?”  For a popular writeup of these findings, see Science Daily.
  3. Imitation as flattery:  Speaking of engineering proteins, an article in Science Daily discussed recent attempts to imitate the folding of DNA and protein for nanotechnology.  A German team said, “we can now build a diversity of three-dimensional nanoscale machine parts, such as round gears or curved tubes or capsules.  Assembling those parts into bigger, more complex and functional devices should be possible.”  A biophysicist on the team added, “We expect many benefits if only we could build super-miniaturized devices on the nanoscale using materials that work robustly in the cells of our bodies – biomolecules such as DNA.”
  4. Diverse origami: Science Daily reported on work at Rice University to study the forces that bind proteins together.  In passing the article explained the design of these gems:

    “Proteins are the workhorses of biology.  Each protein is a string of amino acids that are attached end to end, like a strand of pearls.  The order of the amino acids comes from DNA blueprints, but the order itself doesn’t tell scientists what the protein is designed to do.  That’s because each protein folds in upon itself shortly after its made, much like a strand of pearls curls up as it’s dropped into someone’s palm.
        Unlike the pearls, which might fall this way or that depending upon how they’re dropped, proteins fold the same way every time.  That’s important, because when they misfold, they cannot function properly and in some cases can make people sick.

    No mention was made of how a blind process like evolution could have achieved precision folding of a strand of pearls every time.

  5. One-handed trick: Speaking of design, biophysicists at New York University are excited about designing catalysts that can pick out or manufacture one-handed molecules like cells can.  “Many naturally occurring biopolymers (i.e., proteins, RNA, DNA) owe their unique properties to their well-defined three-dimensional structures,” they said in PNAS2  “These attributes have inspired the design and synthesis of folded architectures with functions ranging from molecular recognition to asymmetric catalysis.”  Sure enough, they discovered a way to do this.  The production of an endless supply of optically pure (one-handed) enantiomers (molecules that come in two hands) could have many applications, particularly when these are polymerized into “foldamers” (chains that fold into specific shapes).  “The transfer of chiral information from a folded scaffold can enable the use of a diverse assortment of embedded achiral catalytic centers, promising a generation of synthetic foldamer catalysts for enantioselective transformations that can be performed under a broad range of reaction environments.”  That’s one of the wonders of the cell – the ability to catalyze reactions like this at room temperature.  Techniques they are designing at their Molecular Design Institute are “promising extraordinary versatility for designing catalysts that can be tailored for a broad range of substrates and reaction environments.”

That last paper mentioned evolution one time in passing:

In living systems, biopolymer catalysts have evolved to accelerate specific biologically relevant transformations.  In contrast, synthetic catalysts must often be designed for nonbiological transformations to be performed in abiotic solvents, pH regimes, temperatures, and pressures that are incompatible with retention of biopolymer structure and activity.  Proteins, however, rely on a limited repertoire of amino acid monomers and require substantial chain lengths to achieve significant structural organization.

It’s clear that they did not attempt to explain how “biopolymer catalysts have evolved.”  They also did not discuss the remarkable ability of living systems to distinguish between left- and right-handed members of chiral molecules – a feature absent from non-living systems.  Their work, instead, demonstrates that achieving enantioselectivity by artificial means requires intelligent design.

1.  Ronald S. Rock, “A new direction for titin pulling, ” Proceedings of the National Academy of Sciences August 5, 2009, doi: 10.1073/pnas.0906989106.
2.  Maayan, Ward and Kirshenbaum, “Folded biomimetic oligomers for enantioselective catalysis,” Proceedings of the National Academy of Sciences, August 10, 2009, doi: 10.1073/pnas.0903187106.

A simple study of probability (see online book; also Stephen Meyer’s new book Signature in the Cell) would have convinced the NYU team that enantioselective catalysts made of “substantial chain lengths” could not have evolved.  Living things needed the selectivity before life was even possible.  That would leave only chance as a means getting the catalysts in the first place.  Is that even conceivably possible under ideal conditions?  Read chapter 3 and see.
    Evolution collapses in a heap under the selective pressure of detailed investigations into biophysics.  It becomes a tangled web with no function.  In some cases, the misfolded chain of reasoning becomes toxic and can make people sick.  It gums up the works of science, producing a kind of Alzheimer’s syndrome that makes people forget their Maker.  It paralyzes rational thought.  The NYU reference to evolution, following the formula “[complex systems a, b, and c] have evolved,” shows another symptom: the knee jerk reaction.  Pray that uninfected biophysics finds a cure soon for this debilitating malady.

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