Methionine as a molecular chameleon

Or why it is disproportionately represented in the universe of protein-protein interactions

Methionine as a "molecular acrobat".

An oldie but goodie from Samuel Gellman (Wisconsin). Methionine appears to be unusually dominant at protein-protein binding interfaces. Earlier studies showed that this was likely due to its unbranched side chain displaying greater flexibility (relative to leucine and isoleucine). Gellman expands on this hypothesis and conjectures that two properties of methionine in particular lead to it conferring plasticity on binding interfaces:

One is the relatively small energy difference between gauche and anti conformations - ~0.2 kcal/mol compared to a more typical 0.8 kcal/mol value for hydrocarbons. This small energy difference leads to an almost flat conformational landscape and makes it easy for the side chain to adopt multiple conformations necessary for binding. Secondly, the relatively large polarizability of sulfur relative to carbon enables methionine to have a larger dispersion-based affinity for nonpolar atoms, contributing to high binding affinity between extensively nonpolar surfaces.

Gellman also speculates that being able to tune the oxidation state of sulfur (S ---> S=O) by enzymes enables biological systems to quickly turn redox potentials on and off. Searching the literature locates a 2006 reference suggesting that oxidized sulfur in methionines can interact better with aromatic residues in proteins. More recent references indicate extensive methionine-aromatic interactions in the PDB; more than 10,000 structures contain this motif occurring more than 10 times.

Overall, then, methionine is a remarkable molecular chameleon. Driven by fundamental physical organic chemical principles, it can easily adopt a variety of conformations and shape-shift itself, both in structure and conformation, to interact with a variety of protein partners. A valuable invention from nature's molecular toolkit!