Enzymes Chew Like Pac-Man
Evidence is growing that many enzymes have moving parts. They act like scissors, clamps and little pac-mans. When precisely-folded chains of amino acids emerge from the ribosome, they fold into unique shapes with the aid of chaperones. But those shapes are not static globs. They move, say Dmitry A. Kondrashov and George N. Phillips, Jr. (U. of Wisconsin). Writing in Structure,1 they describe some of the “molecular mastication mechanics” of these amazing machines:
Computational prediction of global protein motion… suggests that enzymatic active sites tend to be placed near the hinges of the “jaws” of enzyme structures.
Proteins self-organize into exquisitely precise structures, but the actual conformation of a protein fluctuates, and almost never coincides exactly with the average structure observed via X-ray crystallography or other methods. Mounting evidence suggests that these induced motions play specific and essential roles in protein function…. (Emphasis added in all quotes.)
Proteins are so tiny, the motions are very hard to observe. The authors describe the various techniques that try to shed light on “the central question: do these motions contribute to enzyme function?” It appears they do:
Stabilization of the transition state relative to the substrate is thought to be the key to enzymatic efficiency. Static effects clearly play a major part via the electrostatic contribution of the positioning of polar residues. The existence of a “dynamic effect,” however, is controversial, specifically the proposition that enzymes can channel thermal vibrational energy into modes co-directional with the reaction coordinate, thus making barrier crossing more likely. Nevertheless, evidence is accreting to indicate a link between well-defined global motions and catalysis.
After the technical jargon, they lighten up and explain this for the rest of us with some everyday comparisons:
Computation of the normal modes of motion allowed the determination of the “hinges” or pivot points that separate regions of the protein moving in opposite directions, much like the end of a nutcracker. In the vast majority of the enzymes studied, the catalytic residues were found to be located in a predicted hinge region…. This finding contributes a bioinformatic dimension to the field of functional protein dynamics and may allow improved functional annotation for the flood of newly solved protein structures. The results also suggest an enhanced role for the global protein structure, which often has been viewed as a scaffold supporting the active site. The study adds to the growing body of evidence that the fold determines global protein dynamics, suggesting a mechanism for allosteric signal transduction, functional impact of distant mutations, and other effects not explained by the chemistry of the active site. In this view, enzymatic structures resemble a Pac-Man icon, with active sites located in the wedge-shaped opening, and the structure responsible for the “chewing” motion of the “mouth.”
What this means is that the whole protein – all the amino acids, even those distant from the active site, are involved. It is possible that they contribute to orienting the substrate into the active site and stabilizing it once it makes contact, like a vise grip. Moving parts might also contribute to the release of the substrate after catalysis is complete. The structure might strip off solvents before the substrate reaches the active site, resulting in more efficient catalysis. Even short fragments distant from the hinge might contribute an essential part of the overall function.
Viewing enzymes as dynamic machines opens up new avenues for investigation, they envision. The specific sequences in all the parts of the enzyme would require closer scrutiny; they might have moving parts as well. At least, it is an idea to chew on, they conclude; “The relative importance of topology and sequence for protein dynamics and function needs to be investigated, in order to add more teeth to the masticating view of enzyme dynamics.”
1Dmitry A. Kondrashov and George N. Phillips, Jr, “Molecular Mastication Mechanics,” Structure, Volume 13, Issue 6, June 2005, pages 836-837, doi:10.1016/j.str.2005.05.004.
Wonderful thoughts, devoid of evolutionary speculation. Enzymes can no longer be viewed as floating wads of amino acid gunk, and not even as rigid tools like screwdrivers and hammers. Now, we see them as power tools: “exquisitely precise structures” with moving parts, each part contributing to the task at hand. This means that enzymes cannot tolerate many mutations. Previously, biochemists thought that the active site alone was the most intolerant of mutations, but if this emerging picture of dynamic action is correct, even short sequences of amino acids distant from the active site may play vital roles in the overall function. The game is not getting any easier for the Darwinists as Pac-Man keeps chewing through their assumptions.