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Several recent works have shown that protein structure can predictsite-specific evolutionary sequence variation. In particular, sites that areburied and/or have many contacts with other sites in a structure have beenshown to evolve more slowly, on average, than surface sites with few contacts.Here, we present a comprehensive study of the extent to which numerousstructural properties can predict sequence variation. The quantities weconsidered include buriedness (as measured by relative solvent accessibility),packing density (as measured by contact number), structural flexibility (asmeasured by B factors, root-mean-square fluctuations, and variation in dihedralangles), and variability in designed structures. We obtained structuralflexibility measures both from molecular dynamics simulations performed on 9non-homologous viral protein structures and from variation in homologousvariants of those proteins, where available. We obtained measures ofvariability in designed structures from flexible-backbone design in the Rosettasoftware. We found that most of the structural properties correlate with sitevariation in the majority of structures, though the correlations are generallyweak (correlation coefficients of 0.1 to 0.4). Moreover, we found thatburiedness and packing density were better predictors of evolutionary variationthan was structural flexibility. Finally, variability in designed structureswas a weaker predictor of evolutionary variability than was buriedness orpacking density, but it was comparable in its predictive power to the beststructural flexibility measures. We conclude that simple measures of buriednessand packing density are better predictors of evolutionary variation than aremore complicated predictors obtained from dynamic simulations, ensembles ofhomologous structures, or computational protein design.

Predicting evolutionary site variability from structure in viral proteins: buriedness, packing, flexibility, and design