Biology subjects

Julian Echave

Publications and source records attributed to Julian Echave.

3 recordsLinked to original sources

bioRxiv2016

Biophysical models of protein evolution: Understanding the patterns of evolutionary sequence divergence

For decades, rates of protein evolution have been interpreted in terms of the vague concept of \"functional importance\". Slowly evolving proteins or sites within proteins were assumed to be more functionally important and thus subject to stronger selection pressure. More recently, biophysical models of protein evolution, which combine evolutionary theory with protein biophysics, have completely revolutionized our view of the forces that shape sequence divergence. Slowly evolving proteins have been found to evolve slowly because of selection against toxic mis-folding and misinteractions, linking their rate of evolution primarily to their abundance. Similarly, most slowly evolving sites in proteins are not directly involved in function, but mutating them has large impacts on protein structure and stability. Here, we review the studies of the emergent field of biophysical protein evolution that have shaped our current understanding of sequence divergence patterns. We also propose future research directions to develop this nascent field.

Biophysics↗

bioRxiv2014

Too packed to change: site-specific substitution rates and side-chain packing in protein evolution

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 sites C and the other C. According to a mechanistic stress model proposed recently, rates are determined by packing because mutating packed sites stresses and destabilizes the proteins active conformation. While WCN is a measure of C packing, mutations replace side chains, which prompted us to consider whether a sites 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 (WCN{rho}) explains 39.1% of among-sites rate variation, larger than main-chain contact density (WCN) which explains 32.1%. More importantly, the independent contribution of WCN is only 0.7%. Thus, as predicted by the stress theory, site-specific evolutionary rates are determined by side-chain packing.

Biophysics↗

bioRxiv2014

Relationship between protein thermodynamic constraints and variation of evolutionary rates among sites

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 ({Delta}{Delta}G) 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 ({Delta}{Delta}G*). 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.

Biophysics↗