Substitution rates predicted by stability-constrained models of protein evolution are not consistent with empirical data (original) (raw)
2017, Molecular biology and evolution
Protein structures strongly influence molecular evolution. In particular, the evolutionary rate of a protein site depends on the number of its native contacts. Stability constrained models of protein evolution consider this influence of protein structure on evolution by predicting the effect of mutations on the stability of the native state, but they currently neglect how mutations affect the protein structure. These models predict that buried protein sites with more native contacts are more constrained by natural selection and less variable, as observed. Nevertheless, previous work did not consider the stability against compact misfolded conformations, although it is known that the negative design that destabilizes these misfolded conformations influences protein evolution significantly. Here we show that stability constrained models that consider misfolding predict that site-specific sequence entropy and substitution rate peak at amphiphilic sites with an intermediate number of co...
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