Bonnet Pascal, Bryce Richard A
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, UK.
Protein Sci. 2004 Apr;13(4):946-57. doi: 10.1110/ps.03129704.
We report molecular dynamics calculations of neuraminidase in complex with an inhibitor, 4-amino-2-deoxy-2,3-didehydro-N-acetylneuraminic acid (N-DANA), with subsequent free energy analysis of binding by using a combined molecular mechanics/continuum solvent model approach. A dynamical model of the complex containing an ionized Glu119 amino acid residue is found to be consistent with experimental data. Computational analysis indicates a major van der Waals component to the inhibitor-neuraminidase binding free energy. Based on the N-DANA/neuraminidase molecular dynamics trajectory, a perturbation methodology was used to predict the binding affinity of related neuraminidase inhibitors by using a force field/Poisson-Boltzmann potential. This approach, incorporating conformational search/local minimization schemes with distance-dependent dielectric or generalized Born solvent models, correctly identifies the most potent neuraminidase inhibitor. Mutation of the key ligand four-substituent to a hydrogen atom indicates no favorable binding free energy contribution of a hydroxyl group; conversely, cationic substituents form favorable electrostatic interactions with neuraminidase. Prospects for further development of the method as an analysis and rational design tool are discussed.
我们报告了神经氨酸酶与抑制剂4-氨基-2-脱氧-2,3-二脱氢-N-乙酰神经氨酸（N-DANA）复合物的分子动力学计算结果，并随后使用分子力学/连续介质溶剂模型相结合的方法对结合自由能进行了分析。发现含有离子化谷氨酸119氨基酸残基的复合物动力学模型与实验数据一致。计算分析表明，抑制剂与神经氨酸酶结合自由能的主要成分是范德华力。基于N-DANA/神经氨酸酶分子动力学轨迹，采用微扰方法，利用力场/泊松-玻尔兹曼势预测相关神经氨酸酶抑制剂的结合亲和力。这种方法结合了构象搜索/局部最小化方案以及距离依赖介电常数或广义玻恩溶剂模型，正确地识别出了最有效的神经氨酸酶抑制剂。关键配体的四个取代基突变为氢原子表明，羟基对结合自由能没有有利贡献；相反，阳离子取代基与神经氨酸酶形成有利的静电相互作用。文中还讨论了将该方法进一步开发为分析和合理设计工具的前景。
