Eyal Eran, Najmanovich Rafael, Edelman Marvin, Sobolev Vladimir
Department of Plant Sciences, Weizmann Institute of Science, Rehovot, Israel.
Proteins. 2003 Feb 1;50(2):272-82. doi: 10.1002/prot.10276.
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.
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。我们分析了一个由393对蛋白质数据库蛋白质组成的非冗余数据集,每对蛋白质的结构在一个氨基酸上不同,以确定突变区域中构象发生变化的残基数量。在91% - 95%的情况下,两个或更少的残基发生了侧链构象变化。如果排除主链位移的突变位点,这一比例增加到97%。大多数重排(超过60%)是由于侧链的固有柔性,这是通过对一组晶体结构被多次测定的蛋白质亚基的对照集进行分析得出的。不同的氨基酸在突变位点附近表现出不同程度的柔性。大的极性或带电荷的残基以及丝氨酸更具柔性,而芳香族氨基酸和半胱氨酸则不然。这种模式在固有侧链柔性以及配体结合位点和突变位点处增加的柔性中都很常见。构象变化的概率与B因子、蛋白质中侧链构象的频率以及溶剂可及性相关。对于芳香族和亲水残基,最后一种趋势比疏水残基更强。我们得出结论,突变区域中预测侧链构象的搜索空间可以有效地受到限制。然而,预测特定侧链构象或根据个体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侧链构象建模的经验规则。