Abstract

HIV-1 protease (HIV-1 PR) is an essential enzyme for the replication process of its virus, and therefore considered an important target for the development of drugs against the acquired immunodeficiency syndrome (AIDS). Our previous study shows that the catalytic mechanism of subtype B/C-SA HIV-1 PR follows a one-step concerted acyclic hydrolysis reaction process using a two-layered ONIOM B3LYP/6-31++G(d,p) method. This present work is aimed at exploring the proposed mechanism of the proteolysis catalyzed by HIV-1 PR and to ensure our proposed mechanism is not an artefact of a single theoretical technique. Hence, we present umbrella sampling method that is suitable for calculating potential mean force (PMF) for non-covalent ligand/substrate-enzyme association/dissociation interactions which provide thermodynamic details for molecular recognition. The free activation energy results were computed in terms of PMF analysis within the hybrid QM(DFTB)/MM approach. The theoretical findings suggest that the proposed mechanism corresponds in principle with experimental data. Given our observations, we suggest that the QM/MM MD method can be used as a reliable computational technique to rationalize lead compounds against specific targets such as the HIV-1 protease.

摘要

HIV-1 蛋白酶 (HIV-1 PR) 是其病毒复制过程中必不可少的酶，因此被认为是开发针对获得性免疫缺陷综合征 (AIDS) 的药物的重要目标。我们之前的研究表明，亚型 B/C-SA HIV-1 PR 的催化机制遵循使用两层 ONIOM B3LYP/6-31++G(d,p) 方法的一步协同无环水解反应过程。目前的工作旨在探索 HIV-1 PR 催化的蛋白水解的拟议机制，并确保我们提出的机制不是单一理论技术的产物。因此，我们提出了适用于计算非共价配体/底物-酶结合/解离相互作用的潜在平均力 (PMF) 的伞形采样方法，该方法为分子识别提供了热力学细节。自由活化能结果是根据混合 QM(DFTB)/MM 方法中的 PMF 分析计算的。理论研究结果表明，所提出的机制原则上与实验数据一致。鉴于我们的观察，我们建议 QM/MM MD 方法可用作可靠的计算技术，以合理化针对特定目标（如 HIV-1 蛋白酶）的先导化合物。