Protein side-chain rearrangement in regions of point mutations
Protein side-chain rearrangement in regions of point mutations
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DOI：
10.1002/prot.10276
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发表时间：
2003-02-01
期刊：
影响因子：
--
通讯作者：
Sobolev, V
中科院分区：
文献类型：
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作者：
Eyal, E;Najmanovich, R;Sobolev, V
预测点突变后氨基酸侧链重排的一个主要问题是潜在的巨大搜索空间。我们分析了393个蛋白质数据库蛋白质对的非冗余数据集，每个蛋白质对由一个氨基酸组成的结构不同，以确定突变区域中改变构象的残基的数量。在91-95%的情况下，两个或更少的残基发生了侧链构象变化。如果排除有脊椎移位的突变位点，这一数字增加到97%。大多数重排(超过60%)是由于侧链固有的灵活性，这是通过对一组控制蛋白质亚单位的分析得出的，这些蛋白质亚单位的晶体结构被多次确定。不同的氨基酸在突变部位附近表现出不同程度的灵活性。大极性或带电残基，以及丝氨酸更具弹性，而芳香氨基酸和半胱氨酸则不那么灵活。这种模式是固有的侧链灵活性以及配体结合位点和突变位点灵活性增加的共同特征。构象改变的概率与B因子、蛋白质中侧链构象的频率和溶剂可及性有关。最后一种趋势是芳香族和亲水性残基比疏水性残基更强。我们的结论是，预测突变区域侧链构象的搜索空间可以得到有效的限制。然而，预测特定侧链构象或根据个别现有结构检查预测的总体能力是有限的。这些发现可能有助于推导出模拟侧链构象的经验规则。(C)2002年Wiley-Liss，Inc.
A major problem in predicting amino acid side-chain rearrangements following point mutations is the potentially large search space. We analyzed a nonredundant data set of 393 Protein Data Bank protein pairs, each consisting of structures differing in one amino acid, to determine the number of residues changing conformation in the region of mutation. In 91-95% of cases, two or fewer residues underwent side-chain conformational change. If mutation sites with backbone displacements were excluded, the number increased to 97%. The majority of rearrangements (over 60%) were due to the inherent flexibility of side-chains, as derived from analysis of a control set of protein subunits whose crystal structures were determined more than once. Different amino acids demonstrated different degrees of flexibility near mutation sites. Large polar or charged residues, and serine, are more flexible, while the aromatic amino acids, and cysteine, are less so. This pattern is common to the inherent side-chain flexibility, as well as the increased flexibility at ligand binding sites and mutation sites. The probability for conformational change was correlated with B-factor, frequency of the side-chain conformation in proteins and solvent accessibility. The last trend was stronger for aromatic and hydrophilic residues than for hydrophobic ones. We conclude that the search space for predicting side-chain conformations in the region of mutation can be effectively restricted. However, the overall ability to predict a particular side-chain conformation, or to check predictions according to individual existing structures, is limited. These findings may be useful in deriving empirical rules for modeling side-chain conformations. (C) 2002 Wiley-Liss, Inc.