中文摘要：

人血白蛋白是血浆中含量最高的蛋白,是一种重要的载体蛋白,能与多种内源性和外源性物质结合。人血白蛋白主要有两个药物结合位点,位点I和位点II,其中位点II的柔性较大,对药物分子的亲和性较高。本文采用分子模拟方法,基于12种结合于位点II的小分子-人血白蛋白晶体结构,分析了相互作用能,发现12种分子的结合以疏水作用为主,静电作用为辅。进一步采用丙氨酸扫描和结合能评价,分析结合部位的关键氨基酸残基,探究结合模式的规律性,发现从位点入口到空腔内部存在静电、疏水和杂合的三层相互作用分布,共同形成了稳定的分子结合。最后采用分子对接和分子动力学模拟,预测了L-色氨酸的结合模式。研究结果有助于深入了解人血白蛋白药物位点II的小分子结合模式,为基于位点II的药物和分离配基的优化设计提供指导。

英文摘要：

Human serum albumin（HSA） is an extracellular protein that has the highest concentration in blood plasma and is a carrier for many small molecules. HSA has an exceptional binding capacity for many endogenous and exogenous ligands, and contains two main binding sites with high affinity for diverse substances, named Site I and Site II. The binding cavity of Site II is more active and has greater ligand affinity than that of Site I. In this study, molecular simulation methods were used to investigate the molecular interactions between Site II and twelve Site II-specific ligands. The results showed that hydrophobic interactions were the main driving force for binding, with electrostatic interactions playing a secondary role. The key residues and binding mode on Site II were identified with the computational alanine-scanning approach. Three layers were found from the entrance to the interior of the binding pocket, contributing electrostatic interactions, hydrophobic interactions and mixed interactions, respectively. Finally, molecular docking and molecular dynamics were used to predict the binding mode of L-tryptophan on Site II. The results provided insights into the binding mode of Site II on HSA, which could guide the design of new Site II-specific drugs and ligands for the efficient separation of HSA.