期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 44, 页码 13567-13572出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1508584112
关键词
coevolution; network inference; coarse-grained; protein folding; protein dynamics
资金
- Engineering and Physical Sciences Research Council [EP/M013898/1]
- Spanish Ministry of Economy and Competitiveness (MINECO) [BIO2012-40205]
- Institut Curie Paris at the Tres Grand Centre de Calcul-CEA, PRACE-3IP Project [FP7 RI-283493, FP7 RI-312763]
- Engineering and Physical Sciences Research Council [EP/M022609/1, EP/L000253/1, EP/M013898/1] Funding Source: researchfish
- EPSRC [EP/M022609/1, EP/L000253/1, EP/M013898/1] Funding Source: UKRI
The analysis of evolutionary amino acid correlations has recently attracted a surge of renewed interest, also due to their successful use in de novo protein native structure prediction. However, many aspects of protein function, such as substrate binding and product release in enzymatic activity, can be fully understood only in terms of an equilibrium ensemble of alternative structures, rather than a single static structure. In this paper we combine coevolutionary data and molecular dynamics simulations to study protein conformational heterogeneity. To that end, we adapt the Boltzmann-learning algorithm to the analysis of homologous protein sequences and develop a coarse-grained protein model specifically tailored to convert the resulting contact predictions to a protein structural ensemble. By means of exhaustive sampling simulations, we analyze the set of conformations that are consistent with the observed residue correlations for a set of representative protein domains, showing that (i) the most representative structure is consistent with the experimental fold and (ii) the various regions of the sequence display different stability, related to multiple biologically relevant conformations and to the cooperativity of the coevolving pairs. Moreover, we show that the proposed protocol is able to reproduce the essential features of a protein folding mechanism as well as to account for regions involved in conformational transitions through the correct sampling of the involved conformers.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据