Evolutionary Processes and Biophysical Mechanisms: Revisiting Why Evolved Proteins Are Marginally Stable

Evolved proteins observed in natural organisms are found to be only marginally stable. Several mechanistic hypotheses have been presented to date to explain this observation. One idea that has been put forward is that active selection prevents proteins from becoming too stable to enable proper function. A second idea is that marginal stability reflects the point of mutation-selection-drift balance, where it is mutational pressure that generates marginal stability. A third idea explored in this issue of Journal of Molecular Evolution is that a physical limit prevents the evolution of more stable proteins rather than an evolutionary process. While the first two notions are based upon specific evolutionary processes, discussion here is aimed at reconciling evolutionary processes with the physics of protein folding, drawing upon the ideas that have been presented.