Stability changes upon mutation of solvent-accessible residues in proteins evaluated by database-derived potentials
Stability changes upon mutation of solvent-accessible residues in proteins evaluated by database-derived potentials
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DOI：
10.1006/jmbi.1996.0226
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发表时间：
1996-04-19
影响因子：
5.6
通讯作者：
Rooman, M
中科院分区：
文献类型：
--
作者：
Gilis, D;Rooman, M
由单个氨基酸的取代引起的肽和蛋白质的稳定性变化，其可以通过实验测量折叠自由能的变化，在这里使用来自已知蛋白质结构的有效电位进行评价。分析集中在溶剂可接近的残基的突变上。这些代表了总共106个突变，在芽孢杆菌RNA酶、噬菌体T4溶菌酶和胰凝乳蛋白酶抑制剂2以及合成螺旋肽中的不同位点引入。假设突变不修改骨架结构，折叠自由能的变化计算使用各种类型的数据库导出的电位，并与测量的比较。发现距离依赖性残基-残基势不足以估计这些突变引起的稳定性变化，因为它们由疏水性相互作用主导，而疏水性相互作用在蛋白质表面不起重要作用。相反，基于主链扭转角倾向的势产生相当好的结果。事实上，对于106个突变中的96个的子集，计算和测量的折叠自由能的变化与0.87的线性相关系数相关。此外，从相关性中排除的10个突变似乎引起骨架结构的修饰或涉及强疏水相互作用，这对于溶剂可接近的残基是非典型的。此外，我们发现，提高用于测量折叠自由能的变化的溶剂的离子强度提高了相关性，因为它往往掩盖静电相互作用。当将在葡萄球菌核酸酶和趋化蛋白中进行的44个突变添加到这106个突变中时，这些突变首先被丢弃，因为它们中的一些被怀疑影响骨架构象或变性状态，测量和计算的折叠自由能变化之间的相关性仍然相当好：150个突变中的135个的相关系数为0.86。主链扭转势在预测稳定性变化方面的成功表明，用于推导这些势的近似是足够的。此外，它表明，局部相互作用沿着链在蛋白质表面占主导地位。(C)1996年学术出版社
The stability changes in peptides and proteins caused by the substitution of a single amino acid, which can be measured experimentally by the change in folding free energy, are evaluated here using effective potentials derived from known protein structures. The analysis is focused on mutations of residues that are accessible to the solvent. These represent in total 106 mutations, introduced at different sites in barnase, bacteriophage T4 lysozyme and chymotrypsin inhibitor 2, and in a synthetic helical peptide. Assuming that the mutations do not modify the backbone structure, the changes in folding free energies are computed using various types of database-derived potentials and are compared with the measured ones. Distance-dependent residue-residue potentials are found to be inadequate for estimating the stability changes caused by these mutations, as they are dominated by hydrophobic interactions, which do not play an essential role at the protein surface. On the contrary, the potentials based on backbone torsion angle propensities yield quite good results. Indeed, for a subset of 96 out of the 106 mutations, the computed and measured changes in folding free energy correlate with a linear correlation coefficient of 0.87. Moreover, the ten mutations that are excluded from the correlation either seem to cause modifications of the backbone structure or to involve strong hydrophobic interactions, which are atypical for solvent-accessible residues. We find furthermore that raising the ionic strength of the solvent used for measuring the changes in folding free energies improves the correlation, as it tends to mask the electrostatic interactions. When adding to these 106 mutations 44 mutations performed in staphylococcal nuclease and chemotactic protein, which were first discarded because some of them were suspected to affect the backbone conformation or the denatured state, the correlation between measured and computed folding free energy changes remains quite good: the correlation coefficient is 0.86 for 135 out of the 150 mutations. The success of the backbone torsion potentials in predicting stability changes indicates that the approximations made for deriving these potentials are adequate. It suggests moreover that the local interactions along the chain dominate at the protein surface. (C) 1996 Academic Press Limited