期刊
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
卷 17, 期 12, 页码 861-880出版社
SPRINGER
DOI: 10.1023/B:JCAM.0000021882.99270.4c
关键词
binding free energy estimation; continuum electrostatics; drug design; HIV-1 protease; LIE method; ligand binding
A method is proposed for the estimation of absolute binding free energy of interaction between proteins and ligands. Conformational sampling of the protein-ligand complex is performed by molecular dynamics ( MD) in vacuo and the solvent effect is calculated a posteriori by solving the Poisson or the Poisson-Boltzmann equation for selected frames of the trajectory. The binding free energy is written as a linear combination of the buried surface upon complexation, SAS(bur), the electrostatic interaction energy between the ligand and the protein, E-elec, and the difference of the solvation free energies of the complex and the isolated ligand and protein, DeltaG(solv). The method uses the buried surface upon complexation to account for the non-polar contribution to the binding free energy because it is less sensitive to the details of the structure than the van der Waals interaction energy. The parameters of the method are developed for a training set of 16 HIV-1 protease-inhibitor complexes of known 3D structure. A correlation coefficient of 0.91 was obtained with an unsigned mean error of 0.8 kcal/mol. When applied to a set of 25 HIV-1 protease-inhibitor complexes of unknown 3D structures, the method provides a satisfactory correlation between the calculated binding free energy and the experimental pIC(50) without reparametrization.
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