Optimization of the GB/SA solvation model for predicting the structure of surface loops in proteins.
Optimization of the GB/SA solvation model for predicting the structure of surface loops in proteins.
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DOI：
10.1021/jp055771
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发表时间：
2006-02
期刊：
影响因子：
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通讯作者：
A. Szarecka;H. Meirovitch
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文献类型：
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作者：
A. Szarecka;H. Meirovitch
隐式溶剂化模型通常相对于小分子获得的实验数据或Poisson-Boltzmann（PB）结果进行优化，其中有时不考虑力场。在以前的研究中，我们已经开发了一个优化程序的环肽和蛋白质的表面环的基础上研究的整个系统和使用的特定力场。因此，该环已经通过简化的溶剂化函数E（tot）= E（FF）（λ = 2 r）+ Sigma（i）sigma（i）A（i）建模，其中E（FF）（λ = nr）是具有距离依赖性介电函数的AMBER力场能量，λ = nr，A（i）是原子i的溶剂可及表面积，并且sigma（i）是其原子溶剂化参数。在优化过程中，环可以自由移动，而蛋白质模板固定在其X射线结构中。为了改善这个模型的结果，在目前的工作中，我们应用我们的优化程序的物理更严格的溶剂化模型，广义玻恩与表面积（GB/SA）（连同所有原子琥珀力场）的建议仍然和同事（J.物理化学。A 1997年，101，3005）。GB/SA模型的六个参数，即P（1）-P（5）和表面积参数sigma（在TINKER包中编程）针对九个循环的“训练”组被重新优化，并且从优化参数的各个集合定义最佳拟合集合。将最佳拟合集和Still的原始参数集（其中Lys、Arg、His、Glu和Asp被充电或中和）应用于训练组以及七个环的“测试”组，并计算能隙和相应的RMSD值。这些基于三组参数的GB/SA结果已经被发现是相当的;然而，令人惊讶的是，它们比先前从上述简化模型获得的结果稍差（例如，较大的能隙）。我们讨论了其他溶剂化模型和未来研究的潜在方向所获得的循环的最新结果。
Implicit solvation models are commonly optimized with respect to experimental data or Poisson-Boltzmann (PB) results obtained for small molecules, where the force field is sometimes not considered. In previous studies, we have developed an optimization procedure for cyclic peptides and surface loops in proteins based on the entire system studied and the specific force field used. Thus, the loop has been modeled by the simplified solvation function E(tot) = E(FF) (epsilon = 2r) + Sigma(i) sigma(i)A(i), where E(FF) (epsilon = nr) is the AMBER force field energy with a distance-dependent dielectric function, epsilon = nr, A(i) is the solvent accessible surface area of atom i, and sigma(i) is its atomic solvation parameter. During the optimization process, the loop is free to move while the protein template is held fixed in its X-ray structure. To improve on the results of this model, in the present work we apply our optimization procedure to the physically more rigorous solvation model, the generalized Born with surface area (GB/SA) (together with the all-atom AMBER force field) as suggested by Still and co-workers (J. Phys. Chem. A 1997, 101, 3005). The six parameters of the GB/SA model, namely, P(1)-P(5) and the surface area parameter, sigma (programmed in the TINKER package) are reoptimized for a "training" group of nine loops, and a best-fit set is defined from the individual sets of optimized parameters. The best-fit set and Still's original set of parameters (where Lys, Arg, His, Glu, and Asp are charged or neutralized) were applied to the training group as well as to a "test" group of seven loops, and the energy gaps and the corresponding RMSD values were calculated. These GB/SA results based on the three sets of parameters have been found to be comparable; surprisingly, however, they are somewhat inferior (e.g, of larger energy gaps) to those obtained previously from the simplified model described above. We discuss recent results for loops obtained by other solvation models and potential directions for future studies.