Browsing by Author "Echave, Julian"

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A mechanistic stress model of protein evolution accounts for site-specific evolutionary rates and their relationship with packing density and flexibility
(2014-04-09)
Huang, Tsun-Tsao
;
del Valle Marcos, Maria Laura
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Hwang, Jenn-Kang
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Echave, Julian
;
生物資訊及系統生物研究所
Background: Protein sites evolve at different rates due to functional and biophysical constraints. It is usually considered that the main structural determinant of a site's rate of evolution is its Relative Solvent Accessibility (RSA). However, a recent comparative study has shown that the main structural determinant is the site's Local Packing Density (LPD). LPD is related with dynamical flexibility, which has also been shown to correlate with sequence variability. Our purpose is to investigate the mechanism that connects a site's LPD with its rate of evolution. Results: We consider two models: an empirical Flexibility Model and a mechanistic Stress Model. The Flexibility Model postulates a linear increase of site-specific rate of evolution with dynamical flexibility. The Stress Model, introduced here, models mutations as random perturbations of the protein's potential energy landscape, for which we use simple Elastic Network Models (ENMs). To account for natural selection we assume a single active conformation and use basic statistical physics to derive a linear relationship between site-specific evolutionary rates and the local stress of the mutant's active conformation. We compare both models on a large and diverse dataset of enzymes. In a protein-by-protein study we found that the Stress Model outperforms the Flexibility Model for most proteins. Pooling all proteins together we show that the Stress Model is strongly supported by the total weight of evidence. Moreover, it accounts for the observed nonlinear dependence of sequence variability on flexibility. Finally, when mutational stress is controlled for, there is very little remaining correlation between sequence variability and dynamical flexibility. Conclusions: We developed a mechanistic Stress Model of evolution according to which the rate of evolution of a site is predicted to depend linearly on the local mutational stress of the active conformation. Such local stress is proportional to LPD, so that this model explains the relationship between LPD and evolutionary rate. Moreover, the model also accounts for the nonlinear dependence between evolutionary rate and dynamical flexibility.
Local Packing Density Is the Main Structural Determinant of the Rate of Protein Sequence Evolution at Site Level
(2014)
Yeh, So-Wei
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Huang, Tsun-Tsao
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Liu, Jen-Wei
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Yu, Sung-Huan
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Shih, Chien-Hua
Functional and biophysical constraints result in site-dependent patterns of protein sequence variability. It is commonly assumed that the key structural determinant of site-specific rates of evolution is the Relative Solvent Accessibility (RSA). However, a recent study found that amino acid substitution rates correlate better with two Local Packing Density (LPD) measures, the Weighted Contact Number (WCN) and the Contact Number (CN), than with RSA. This work aims at a more thorough assessment. To this end, in addition to substitution rates, we considered four other sequence variability scores, four measures of solvent accessibility (SA), and other CN measures. We compared all properties for each protein of a structurally and functionally diverse representative dataset of monomeric enzymes. We show that the best sequence variability measures take into account phylogenetic tree topology. More importantly, we show that both LPD measures (WCN and CN) correlate better than all of the SA measures, regardless of the sequence variability score used. Moreover, the independent contribution of the best LPD measure is approximately four times larger than that of the best SA measure. This study strongly supports the conclusion that a site\'s packing density rather than its solvent accessibility is the main structural determinant of its rate of evolution.
Site-Specific Structural Constraints on Protein Sequence Evolutionary Divergence: Local Packing Density versus Solvent Exposure
(2014-01-01)
Yeh, So-Wei
;
Liu, Jen-Wei
;
Yu, Sung-Huan
;
Shih, Chien-Hua
;
Hwang, Jenn-Kang
Protein sequences evolve under selection pressures imposed by functional and biophysical requirements, resulting in site-dependent rates of amino acid substitution. Relative solvent accessibility (RSA) and local packing density (LPD) have emerged as the best candidates to quantify structural constraint. Recent research assumes that RSA is the main determinant of sequence divergence. However, it is not yet clear which is the best predictor of substitution rates. To address this issue, we compared RSA and LPD with site-specific rates of evolution for a diverse data set of enzymes. In contrast with recent studies, we found that LPD measures correlate better than RSA with evolutionary rate. Moreover, the independent contribution of RSA is minor. Taking into account that LPD is related to backbone flexibility, we put forward the possibility that the rate of evolution of a site is determined by the ease with which the backbone deforms to accommodate mutations.