STRUCTURAL DETERMINANTS OF REPLACEMENT RATE HETEROGENEITY

Abstract

<p> Protein sequences display replacement rate heterogeneity across sites. In an earlier work, half of the causal site-wise variation in replacement rates was explained by a simple linear regression model consisting of terms for the solvent exposure of each residue, distance from the active site, and glycines in unusual main-chain conformations. Replacement rates vary not only across sites, they may also vary over time. In this study, we apply the linear regression model to phylogenies divided into subtrees to see if lineage-specific rate shifts have a structural basis that can be detected by the model. This approach is applied to two different data sets. The first set consists of phylogenies containing two representative structures, divided into subtrees such that one structure is present in each subtree. These structures have little or no obvious functional divergence between them. The model is tested with permutations of subtrees and structures from each subtree. While there is a slight effect of the specific structure on the fit of the model, the specific subtree has a greater effect. The second data set involves homologous structure pairs where the quaternary structure has changed at some point in the phylogeny. These pairs are examined to see how the change in constraint on the new interface sites affect the replacement rate, and its relationship with other structural factors. We find that the unique interfaces are as conserved as the shared ones, and they exhibit a different relationship between replacement rates and indicators of constraint than the shared interfaces or other protein sites. We also find that the unique interfaces display characteristic amino acid preferences that may identify interfaces which are still in the process of stabilizing. </p>