@article {Marcos013359, author = {Mar{\'\i}a Laura Marcos and Julian Echave}, title = {Too packed to change: site-specific substitution rates and side-chain packing in protein evolution}, elocation-id = {013359}, year = {2014}, doi = {10.1101/013359}, publisher = {Cold Spring Harbor Laboratory}, abstract = {In protein evolution, due to functional and biophysical constraints, the rates of amino acid substitution differ from site to site. Among the best predictors of site-specific rates is packing density. The packing density measure that best correlates with rates is the weighted contact number (WCN), the sum of inverse square distances between the site{\textquoteright}s Cα and the other Cα. According to a mechanistic stress model proposed recently, rates are determined by packing because mutating packed sites stresses and destabilizes the protein{\textquoteright}s active conformation. While WCN is a measure of Cα packing, mutations replace side chains, which prompted us to consider whether a site{\textquoteright}s evolutionary divergence is constrained by main-chain packing or side-chain packing. To address this issue, we extended the stress theory to model side chains explicitly. The theory predicts that rates should depend solely on side-chain packing. We tested these predictions on a data set of structurally and functionally diverse monomeric enzymes. We found that, on average, side-chain contact density (WCNρ) explains 39.1\% of among-sites rate variation, larger than main-chain contact density (WCNα) which explains 32.1\%. More importantly, the independent contribution of WCNα is only 0.7\%. Thus, as predicted by the stress theory, site-specific evolutionary rates are determined by side-chain packing.}, URL = {https://www.biorxiv.org/content/early/2014/12/30/013359}, eprint = {https://www.biorxiv.org/content/early/2014/12/30/013359.full.pdf}, journal = {bioRxiv} }