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

Computational and Structural Biotechnology Journal
Pierre Tufféry, Sjoerd de Vries

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 result...Continue Reading

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Methods Mentioned

BETA
protein folding

Software Mentioned

PSI
ELM
BLAST
INPS
clustal omega
Rosetta
CS
JS
SAAMBE
PSeqGen

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