title: Relationship between protein thermodynamic constraints and variation of evolutionary rates among sites.
abstract: Evolutionary-rate variation among sites within proteins depends on functional and biophysical properties that constrain protein evolution. It is generally accepted that proteins must be able to fold stably in order to function. However, the relationship between stability constraints and among-sites rate variation is not well understood. Here, we present a biophysical model that links the thermodynamic stability changes due to mutations at sites in proteins ([Formula: see text]) to the rate at which mutations accumulate at those sites over evolutionary time. We find that such a 'stability model' generally performs well, displaying correlations between predicted and empirically observed rates of up to 0.75 for some proteins. We further find that our model has comparable predictive power as does an alternative, recently proposed 'stress model' that explains evolutionary-rate variation among sites in terms of the excess energy needed for mutants to adopt the correct active structure ([Formula: see text]). The two models make distinct predictions, though, and for some proteins the stability model outperforms the stress model and vice versa. We conclude that both stability and stress constrain site-specific sequence evolution in proteins.
authors: Escuela de Ciencia y Tecnología, Universidad Nacional de San Martín, Martín de Irigoyen 3100, 1650 San Martín, Buenos Aires, Argentina.
authors: Julian
authors: J
authors: Echave
authors: Eleisha L
authors: EL
authors: Jackson
authors: Claus O
authors: CO
authors: Wilke
mesh_terms: D000595:Amino Acid Sequence; D019143:Evolution, Molecular; D008957:Models, Genetic; D009154:Mutation; D013816:Thermodynamics