Functionality and the evolution of marginal stability in proteins: inferences from lattice simulations

It has been known for some time that many proteins are marginally stable. This has inspired several explanations. Having noted that the functionality of many enzymes is correlated with subunit motion, flexibility, or general disorder, some have suggested that marginally stable proteins should have an evolutionary advantage over proteins of differing stability. Others have suggested that stability and functionality are contradictory qualities, and that selection for both criteria results in marginally stable proteins, optimised to satisfy the competing design pressures. While these explanations are plausible, recent research simulating the evolution of model proteins has shown that selection for stability, ignoring any aspects of functionality, can result in marginally stable proteins because of the underlying makeup of protein sequence-space. We extend this research by simulating the evolution of proteins, using a computational protein model that equates functionality with binding and catalysis. In the model, marginal stability is not required for ligand-binding functionality and we observe no competing design pressures. The resulting proteins are marginally stable, again demonstrating that neutral evolution is sufficient for explaining marginal stability in observed proteins.