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Collective Motion: A New Level of Design Found in Proteins


A "previously unidentified mechanism for modulating protein affinity" has come to light. A team of scientists at the Max Planck Institute for Biochemical Chemistry, publishing in the Proceedings of the National Academy of Sciences, has identified new functional roles for collective motions within protein molecules. These motions, referred to as allostery, allow one end of the protein to affect a distant part through what is termed "allosteric communication."

Intermolecular interactions are one of the key mechanisms by which proteins mediate their biological functions. For many proteins, these interactions are enhanced or suppressed by allosteric networks that couple distant regions together. The mechanisms by which these networks function are just starting to be understood, and many of the important details have yet to be uncovered. In particular, the role of intrinsic protein motion and kinetics remains particularly poorly characterized. [Emphasis added.]

This is cutting-edge research. The team studied a common protein named ubiquitin which, as the name implies, is ubiquitous in the cell. It serves as a molecular "tag" on other molecules slated for degradation by the proteasome. As such, it needs to form connections with the proteasome and with a variety of other proteins. What they found is that distant parts of the molecule could affect binding affinity of other parts through motions transmitted throughout the entire molecule.

To determine how this collective motion influences binding and other functions of ubiquitin (e.g., presence of different covalent linkages), we performed an extensive structural bioinformatics survey of known ubiquitin crystal structures. Because the peptide bond conformation was the most recognizable feature of the collective mode, we used its conformation as a "marker" for structural discrimination. The most significant relationship we found was the universal association between the NH-in state and binding to the ubiquitin-specific protease (USP) family of deubiquitinases (Fig. S11). This association has been previously noted and is surprising because the peptide bond is at least 6.8 Å from any USP (Fig. 3A).

By comparing mutants with wild-type forms, the team found several kinds of motion that involve twisting, rocking and stretching. Mutations on a peptide bond between two specific amino acid residues, in particular, had a surprising effect, reducing binding affinity by a factor of 10 (or abolishing it altogether). This suggests low tolerance for mutation.

They found "strong allosteric coupling between opposite sides of the protein" in some cases. "Given the relative subtlety of the expansion and contraction" of allosteric interactions, they found it "surprising" again that two different states could produce large effects. It implies that ubiquitin and its ligand "appear to adapt their conformations mutually to establish a complementary binding interaction" for best fit at the appropriate times.

One mutant showed a two-fold weaker affinity for its particular USP. "Although this change may seem like a moderate effect," they note, "it is actually surprisingly large and highly significant when one considers that it is allosterically triggered by the simple rotation of a solvent-exposed peptide bond on a distal side of the protein."

These motions are so rapid -- on the order of microseconds -- they were not really considered significant until recently. Other motions they mention, like "pincer time" and "tumbling time," occur on different time scales, the former being quicker, the latter being much slower. This may suggest a kind of timing code for different functions.

Their conclusions reveal a significant new area of study: switch-controlled "allosteric communication" in protein molecules:

This study revealed an allosteric switch affecting protein-protein binding through collective protein motion at the microsecond time scale.... Whereas most known microsecond to millisecond time-scale motions involve excursions to excited, lowly populated states, this motion occurs between two ground state ensembles with nearly equal populations (NH-in and NHout). Strikingly, the peptide bond conformation is allosterically coupled through a diverse set of interactions that triggers contraction/ expansion of the entire domain. This type of global domain motion reveals a previously unidentified mechanism for modulating protein affinity. The presence of this allosteric network suggests there may be heretofore undiscovered ways in which macromolecular assemblies and covalent linkages regulate ubiquitin binding. More broadly, this study demonstrates how relatively modest changes in hydrogen bond networks and the protein backbone can bring about distant changes in protein conformation and binding affinity.

We encounter, therefore, a whole new level of specificity in protein architecture. It's not the old picture of an active site surrounded by haphazard amino acid residues. Any change could affect the allosteric communication of the whole protein. Clearly, mutants were less able to take advantage of the benefits of collective motion.

How did an unguided process arrive at a molecular machine that not only grips its substrate and catalyzes a reaction efficiently, but moves with intrinsic twists and stretches to improve the grip? The design specs for proteins just shot up a notch, and along with them, the challenges to Darwinian evolution.

Image: Ubiquitin, by Thomas Splettstoesser (www.scistyle.com) (Own work) [CC0], via Wikimedia Commons.