人类免疫缺陷病毒蛋白酶(HIV-1 PR)是艾滋病毒生命循环所必须的病毒编码酶，是抗HIV药物的重要靶位点。HIV治疗上的兴趣在于研究这种酶的机理及结构特性，进而获得这种酶催化机理的本质。众所周知，氢键通常在酶的催化中发挥着关键性的作用。而目前，只有通过QM/MM方法才可能研究这些问题。为了适应这种需求，将量子力学方法与分子力学结合起来，建立并发展适合HIV-1 PR体系的更为精密的量子力学组合原子-键电负性均衡方法融合进分子力场(QM/ABEEM/MM)模型，研究HIV-1PR和抑制剂之间的相互作用行为、结构特性等，主要讨论HIV-1PR体系静电相互作用，探讨氢键网络、分析动力学及热力学性质，讨论化学特性和生物活性等问题。应用QM/ABEEM/MM模型研究HIV-1PR结构特性及其催化水解的分子机理，并为寻找具有高效低毒、药动学特性好的新一代蛋白酶类抑制剂奠定理论基础。

Do you want to know the property and mechanism about HIV-1 PR? We will investigate the above problems in terms of QM/ABEEM/MM method in our project. The enzyme protease from HIV-1 PR is one of the main targets for therapeutic intervention in AIDS. The therapeutical interest of the HIV-1 PR has spurred a number of mechanistic and structural studies directed to the elucidation of the catalytic mechanism of this enzyme. The empirical force field based methods are useful for describing interactions of the catalytic aspartyl pair, but they are not rigorous enough. Approaches based on ab initio quantum mechanics (QM) are rigorous but slow for the studies of macromolecules of biological interest. In order to accelerate QM calculations the hybrid QM/MM method has been developed for the study of enzyme catalysis. Furthermore, it is well known that hydrogen bonds often play a crucial role in enzymatic catalysis. Today such a study is possible only using quantum mechanic/molecular mechanic approaches (QM/MM). To meet this demand, in our project the hybrid QM/ABEEM/MM method will be established for the HIV systems. The interaction and structural character between the HIV-1 PR and substrate will be studied by the QM/ABEEM/MM method. The electrostatic interactions, hydrogen bond network, kinetic and thermodynamic properties, chemical properties and biological activity, etc., of the HIV-1 PR system will be discussed. However, HIV-1 quickly mutates to confer resistance to the administered drugs, leading to failure of the treatment regimen in many cases. So the molecular mechanisms of PR inhibition and activity must be comprehended to develop new strategies to overcome drug resistance. In addition, the hydrolysis mechanism of the HIV-1PR, the optimal reaction channel, the activation energy and other chemical thermodynamic properties will be investigated by the QM/ABEEM/MM method in detail in our project.This work will help to develop a new generation of protease inhibitors with high efficiency, low toxicity, and pharmacokinetic characteristics.