布洛芬与人血白蛋白位点II动态结合过程的分子模拟:一种结合途径分析

人血白蛋白（HSA）主要有两个药物结合位点，位点I和位点Ⅱ，许多小分子优先结合在位点Ⅱ上，包括抗炎类药物布洛芬。本文采用分子模拟方法研究了布洛芬小分子与HSA位点Ⅱ结合的动态过程，探讨了二者的结合机制。首先构建了50个随机分布的布洛芬与HSA复合物体系，经50 ns分子动力学模拟，其中一个布洛芬分子稳定结合于位点Ⅱ。基于该分子的运动轨迹分析，发现布洛芬的结合可分为四个阶段，即远程吸引、表面结合调整、进入位点Ⅱ空腔和稳定结合。比较范德华和静电相互作用能，发现初期以静电吸引为主，中期在HSA表面的两个极性区域间调整，逐步转移至位点Ⅱ附近；然后在位点Ⅱ入口处的极性残基和附近疏水残基的共同作用下，布洛芬进入位点Ⅱ空腔；进入空腔后，静电和疏水共同作用形成稳定结合。在结合过程中，位点Ⅱ附近的蛋白表面发生明显改变，体现出一定的“诱导契合”作用，同时分子模拟得到的结合模式和布洛芬-HSA结合的晶体结构类似。结果表明，分子模拟可以辅助研究小分子和蛋白结合的动态过程，从分子水平阐述相关结合机制。

Molecular Simulations on Dynamic Binding of Ibuprofen onto Site II of Human Serum Albumin: One Potential Way Analysis

Human serum albumin (HSA) has two main drug binding sites termed Site I and Site II. Most small molecules like ibuprofen (a well-known anti-inflammatory drug) bind to Site II preferentially. In this study, molecular simulation methods were used to investigate the dynamic binding process of ibuprofen to Site II. A system of 50 ibuprofen molecules distributed randomly around HSA was constructed. After a 50-ns molecular dynamics simulation, one ibuprofen molecule bound stably to Site II. Based on trajectory analysis of this ibuprofen molecule, the binding process of ibuprofen onto Site II can be divided into four phases:(i) long-range attraction; (ii) adjustment on the surface; (iii) entering to Site II pocket; and (iv) stable binding at Site II. After evaluating van der Waals' and electrostatic interaction energies during the binding process, it was found that the initial major driving force involves electrostatic attractions. Subsequently, ibuprofen locks between two polar regions on the surface near Site II and then moves to Site II. Ibuprofen then enters the pocket of Site II by combinatorial effects of polar and hydrophobic residues nearby the entrance of Site II. Electrostatic and hydrophobic interactions form the stable binding of ibuprofen in Site II. The molecular surface near Site II was observed to change significantly during binding, which indicates an induced fit mechanism. The binding mode obtained with molecular simulations is consistent with the crystal structure of the ibuprofen-HSA complex. The results show that molecular simulations would help to evaluate the dynamic binding processes of small molecules to proteins and improve our understanding of the binding mechanisms at the molecular level.