Pacini Lorenza, Lesieur Claire
University Lyon, CNRS, INSA Lyon, Ecole Centrale de Lyon, UMR5005, Université Claude Bernard Lyon 1, Villeurbanne, France.
Institut Rhônalpin des Systèmes Complexes, IXXI-ENS-Lyon, Lyon, France.
Front Mol Biosci. 2022 Oct 31;9:1035248. doi: 10.3389/fmolb.2022.1035248. eCollection 2022.
Proteins exist for more than 3 billion years: proof of a sustainable design. They have mechanisms coping with internal perturbations (e.g., amino acid mutations), which tie genetic backgrounds to diseases or drug therapy failure. One difficulty to grasp these mechanisms is the asymmetry of amino acid mutational impact: a mutation at position in the sequence, which impact a position does not imply that the mutation at position impacts the position . Thus, to distinguish the influence of the mutation of on from the influence of the mutation of on , position mutational influences must be represented with directions. Using the X ray structure of the third PDZ domain of PDS-95 (Protein Data Bank 1BE9) and mutations, we build a directed network called GCAT that models position mutational influences. In the GCAT, a position is a node with edges that leave the node (out-edges) for the influences of the mutation of the position on other positions and edges that enter the position (in-edges) for the influences of the mutation of other positions on the position. 1BE9 positions split into four influence categories called G, C, A and T going from positions influencing on average less other positions and influenced on average by less other positions (category C) to positions influencing on average more others positions and influenced on average by more other positions (category T). The four categories depict position neighborhoods in the protein structure with different tolerance to mutations.
蛋白质已存在超过30亿年：可持续设计的证明。它们具有应对内部扰动（例如氨基酸突变）的机制，这些机制将遗传背景与疾病或药物治疗失败联系起来。理解这些机制的一个困难在于氨基酸突变影响的不对称性：序列中位置i处的突变影响位置j，并不意味着位置j处的突变会影响位置i。因此，为了区分位置i的突变对位置j的影响与位置j的突变对位置i的影响，位置突变影响必须用方向来表示。利用PDS - 95第三个PDZ结构域的X射线结构（蛋白质数据库1BE9）和突变，我们构建了一个名为GCAT的有向网络，该网络对位置突变影响进行建模。在GCAT中，一个位置是一个节点，有离开该节点的边（出边）表示该位置的突变对其他位置的影响，以及进入该位置的边（入边）表示其他位置的突变对该位置的影响。1BE9的位置分为四个影响类别，称为G、C、A和T，从平均影响其他位置较少且受其他位置影响较少的位置（C类）到平均影响其他位置较多且受其他位置影响较多的位置（T类）。这四个类别描绘了蛋白质结构中对突变具有不同耐受性的位置邻域。
