Tufféry Pierre, de Vries Sjoerd
Université de Paris, BFA, UMR 8251, CNRS, ERL U1133, Inserm, RPBS, F-75013 Paris, France.
Comput Struct Biotechnol J. 2020 Jun 17;18:1790-1799. doi: 10.1016/j.csbj.2020.06.018. eCollection 2020.
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.
蛋白质工程或候选治疗性肽优化是相关序列变体识别至关重要的过程。从一个氨基酸序列开始，替换的选择必须满足不破坏蛋白质结构、不影响起始实体的主要功能特性的目标，同时还要满足增强某些预期特性（如热稳定性、抗降解性等）的条件。在此，我们引入一种新的序列进化方法，该方法通过对序列中每个位置的局部结构保存进行点对点控制，专注于不破坏初始蛋白质结构的目标。对于6种微型蛋白质，我们发现，从单个序列开始，我们的简单方法内在地包含有关位点特异性替换速率异质性的信息，并且它能够重现如在Uniref数据库中可用序列中所观察到的序列多样性。我们表明，我们的方法能够提供关于不进行替换的位置以及为维持结构完整性在给定位置不进行的替换的信息。总体而言，我们的结果表明，沿序列的局部结构的点对点保存是序列进化的一个重要决定因素。
