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The search of sequence variants using a constrained protein evolution simulation approach.

ABSTRACT: Protein engineering or candidate therapeutic peptide optimization are processes in which the identification of relevant sequence variants is critical. Starting from one amino-acid sequence, the choice of the substitutions must meet the objective of not disrupting the structure of the protein, not impacting the main functional properties of the starting entity, while also meeting the condition to enhance some expected property such as thermal stability, resistance to degradation, … Here, we introduce a new approach of sequence evolution that focuses on the objective of not disrupting the structure of the initial protein by embedding a point to point control on the preservation of the local structure at each position in the sequence. For 6 mini-proteins, we find that, starting from a single sequence, our simple approach intrinsically contains information about site-specific rate heterogeneity of substitution, and that it is able to reproduce sequence diversity as can be observed in the sequences available in the Uniref repository. We show that our approach is able to provide information about positions not to substitute and about substitutions not to perform at a given position to maintain structure integrity. Overall, our results demonstrate that point to point preservation of the local structure along a sequence is an important determinant of sequence evolution.

SUBMITTER: Tuffery P

PROVIDER: S-EPMC7355721 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The search of sequence variants using a constrained protein evolution simulation approach.

Tufféry Pierre P de Vries Sjoerd S

Computational and structural biotechnology journal 20200617

Protein engineering or candidate therapeutic peptide optimization are processes in which the identification of relevant sequence variants is critical. Starting from one amino-acid sequence, the choice of the substitutions must meet the objective of not disrupting the structure of the protein, not impacting the main functional properties of the starting entity, while also meeting the condition to enhance some expected property such as thermal stability, resistance to degradation, … Here, we intro ...[more]

PMID: 32695271

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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.

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The search of sequence variants using a constrained protein evolution simulation approach.

Publications

The search of sequence variants using a constrained protein evolution simulation approach.

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