The integration of molecular evolution and protein biophysics is an emerging theme that steadily gained importance during the last 15 years, significantly advancing both fields. The central integrative concept is the stability of the native state, although non-native conformations are increasingly recognized to play a major role, concerning, for example, aggregation, folding kinetics, or functional dynamics. Besides molecular requirements on fitness, the stability of native and alternative conformations is modulated by a variety of factors, including population size, selective pressure on the replicative system, which determines mutation rates and biases, and epistatic effects. We discuss some of the recent advances, open questions, and integrating views in protein evolution, in light of the many underlying trade-offs, correlations, and dichotomies.
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