期刊
JOURNAL OF COMPUTATIONAL CHEMISTRY
卷 23, 期 1, 页码 15-27出版社
WILEY
DOI: 10.1002/jcc.1153
关键词
protein-protein interaction; site-directed mutagenesis; binding free energy; molecular dynamics; continuum model
资金
- NCRR NIH HHS [P41RR-01081] Funding Source: Medline
- NIGMS NIH HHS [GM-29072] Funding Source: Medline
The MM-PBSA (Molecular Mechanics-Poisson-Boltzmann surface area) method was applied to the human Growth Hormone (hGH) complexed with its receptor to assess both the validity and the limitations of the computational alanine scanning approach. A 400-ps dynamical trajectory of the fully solvated complex was simulated at 300 K in a 101 Angstrom x 81 Angstrom x 107 Angstrom water box using periodic boundary conditions. Long-range electrostatic interactions were treated with the particle mesh Ewald (PME) summation method. Equally spaced snapshots along the trajectory were chosen to compute the binding free energy using a continuum solvation model to calculate the electrostatic desolvation free energy and a solvent-accessible surface area approach to treat the nonpolar solvation free energy. Computational alanine scanning was performed on the same set of snapshots by mutating the residues in the structural epitope of the hormone and the receptor to alanine and recomputing the DeltaG(binding). To further investigate a particular structure, a 200-ps dynamical trajectory of an R43A hormone-receptor complex was simulated. By postprocessing a single trajectory of the wild-type complex, the average unsigned error of our calculated Delta DeltaG(binding) is similar to1 kcal/mol for the alanine mutations of hydrophobic residues and polar/charged residues without buried salt bridges. When residues involved in buried salt bridges are mutated to alanine, it is demonstrated that a separate trajectory of the alanine mutant complex can lead to reasonable agreement with experimental results. Our approach can be extended to rapid screening of a variety of possible modifications to binding sites. (C) 2002 John Wiley & Sons, Inc.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据