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Protein evolution along phylogenetic histories under structurally constrained substitution models.

ABSTRACT: MOTIVATION:Models of molecular evolution aim at describing the evolutionary processes at the molecular level. However, current models rarely incorporate information from protein structure. Conversely, structure-based models of protein evolution have not been commonly applied to simulate sequence evolution in a phylogenetic framework, and they often ignore relevant evolutionary processes such as recombination. A simulation evolutionary framework that integrates substitution models that account for protein structure stability should be able to generate more realistic in silico evolved proteins for a variety of purposes. RESULTS:We developed a method to simulate protein evolution that combines models of protein folding stability, such that the fitness depends on the stability of the native state both with respect to unfolding and misfolding, with phylogenetic histories that can be either specified by the user or simulated with the coalescent under complex evolutionary scenarios, including recombination, demographics and migration. We have implemented this framework in a computer program called ProteinEvolver. Remarkably, comparing these models with empirical amino acid replacement models, we found that the former produce amino acid distributions closer to distributions observed in real protein families, and proteins that are predicted to be more stable. Therefore, we conclude that evolutionary models that consider protein stability and realistic evolutionary histories constitute a better approximation of the real evolutionary process.

SUBMITTER: Arenas M

PROVIDER: S-EPMC5221705 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Protein evolution along phylogenetic histories under structurally constrained substitution models.

Arenas Miguel M Dos Santos Helena G HG Posada David D Bastolla Ugo U

Bioinformatics (Oxford, England) 20130912 23

<h4>Motivation</h4>Models of molecular evolution aim at describing the evolutionary processes at the molecular level. However, current models rarely incorporate information from protein structure. Conversely, structure-based models of protein evolution have not been commonly applied to simulate sequence evolution in a phylogenetic framework, and they often ignore relevant evolutionary processes such as recombination. A simulation evolutionary framework that integrates substitution models that ac ...[more]

PMID: 24037213

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Project description:BackgroundStructure conservation constrains evolutionary sequence divergence, resulting in observable sequence patterns. Most current models of protein evolution do not take structure into account explicitly, being unsuitable for investigating the effects of structure conservation on sequence divergence. To this end, we recently developed the Structurally Constrained Protein Evolution (SCPE) model. The model starts with the coding sequence of a protein with known three-dimensional structure. At each evolutionary time-step of an SCPE simulation, a trial sequence is generated by introducing a random point mutation in the current coding DNA sequence. Then, a "score" for the trial sequence is calculated and the mutation is accepted only if its score is under a given cutoff, lambda. The SCPE score measures the distance between the trial sequence and a given reference sequence, given the structure. In our first brief report we used a "global score", in which the same reference sequence, the ancestral one, was used at each evolutionary step. Here, we introduce a new scoring function, the "local score", in which the sequence accepted at the previous evolutionary time-step is used as the reference. We assess the model on the UDP-N-acetylglucosamine acyltransferase (LPXA) family, as in our previous report, and we extend this study to all other members of the left-handed parallel beta helix fold (LbetaH) superfamily whose structure has been determined.ResultsWe studied site-dependent entropies, amino acid probability distributions, and substitution matrices predicted by SCPE and compared with experimental data for several members of the LbetaH superfamily. We also evaluated structure conservation during simulations. Overall, SCPE outperforms JTT in the description of sequence patterns observed in structurally constrained sites. Maximum Likelihood calculations show that the local-score and global-score SCPE substitution matrices obtained for LPXA outperform the JTT model for the LPXA family and for the structurally constrained sites of class i of other members within the LbetaH superfamily.ConclusionWe extended the SCPE model by introducing a new scoring function, the local score. We performed a thorough assessment of the SCPE model on the LPXA family and extended it to all other members of known structure of the LbetaH superfamily.

Dataset Information

Protein evolution along phylogenetic histories under structurally constrained substitution models.

Publications

Protein evolution along phylogenetic histories under structurally constrained substitution models.

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