Wilson C, Gregoret L M, Agard D A
Howard Hughes Medical Institute, Graduate Group in Biophysics, University of California, San Francisco 94143-0448.
J Mol Biol. 1993 Feb 20;229(4):996-1006. doi: 10.1006/jmbi.1993.1100.
We have developed a computational method for accurately predicting the conformation of side-chain atoms when building a protein structure from a known homologous structure. A library of rotamers is used to model the side-chains, allowing an average of five to six different conformations per residue. Local sites of adjacent side-chains are defined throughout the protein, and all combinations of side-chain rotamers are evaluated within each site using a molecular mechanics force field enhanced by the inclusion of a solvation term. At each site, the lowest energy combination of side-chains is identified and added onto the fixed protein backbone. A series of test cases using the refined X-ray structure of alpha-lytic protease has shown that: (1) the force field can correctly predict up to 90% of side-chain rotamers; (2) the assumption of side-chain rotamer geometry is usually a very good approximation; and (3) the complete combinatorial conformation search is able overcome local minima and identify the lowest energy rotamer set for the protein in the absence of a starting bias to the correct structure. Tests with several pairs of homologous proteins have shown that the algorithm is quite successful at predicting side-chain conformation even when the protein backbone used to generate side-chain positions deviates from the correct conformation. The root-mean-square (r.m.s.) deviation of predicted side-chain atoms rises from 1.31 A (average r.m.s.d. 0.73 A) in a test case with the correct backbone to only 2.68 A (1.95 A average r.m.s.d.) in a test case with < 35% homology. The high accuracy of this method suggests that it may be a useful automated tool for modeling protein structure.
我们开发了一种计算方法，用于在根据已知同源结构构建蛋白质结构时准确预测侧链原子的构象。使用一个旋转异构体库来模拟侧链，每个残基平均允许有五到六种不同的构象。在整个蛋白质中定义相邻侧链的局部位点，并使用包含溶剂化项增强的分子力学力场在每个位点评估侧链旋转异构体的所有组合。在每个位点，识别出侧链的最低能量组合并添加到固定的蛋白质主链上。一系列使用α-裂解蛋白酶精细X射线结构的测试案例表明：（1）力场能够正确预测高达90%的侧链旋转异构体；（2）侧链旋转异构体几何形状的假设通常是一个非常好的近似；（3）在没有对正确结构的起始偏差的情况下，完整的组合构象搜索能够克服局部最小值并识别出蛋白质的最低能量旋转异构体集。对几对同源蛋白质的测试表明，即使用于生成侧链位置的蛋白质主链偏离正确构象，该算法在预测侧链构象方面也相当成功。在一个主链正确的测试案例中，预测侧链原子的均方根（r.m.s.）偏差从1.31 Å（平均r.m.s.d. 0.73 Å）上升到在同源性< 35%的测试案例中仅为2.68 Å（平均r.m.s.d. 1.95 Å）。这种方法的高精度表明它可能是一种用于蛋白质结构建模的有用自动化工具。
