Free energy calculations on dimer stability of the HIV protease using molecular dynamics and a continuum solvent model
Free energy calculations on dimer stability of the HIV protease using molecular dynamics and a continuum solvent model
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DOI：
10.1006/jmbi.2000.4057
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发表时间：
2000-11-03
影响因子：
5.6
通讯作者：
Kollman, PA
中科院分区：
文献类型：
--
作者：
Wang, W;Kollman, PA
HIV-I蛋白酶（HIV PR）单体的二聚化是病毒蛋白水解活性和随后产生感染性病毒颗粒的必要先决条件。破坏酶的二聚化可以抑制其活性。我们已经计算了不同的HIV蛋白酶的二聚体之间的相对结合自由能使用分子动力学和连续模型，我们称之为MM/PBSA。我们研究了显性负抑制HIV PR的突变形式的蛋白酶，并发现相对二聚自由能的同源和异源二聚与实验数据一致。我们还开发了一种快速筛选方法，称为虚拟诱变方法，以考虑可能稳定非野生型异二聚体的其他突变。使用这种方法，我们考虑了二聚体界面附近的突变，这可能会导致显性负抑制HIV PR。我们开发的快速方法可用于研究任何配体-蛋白质和蛋白质-蛋白质相互作用，以确定突变，可以提高复合物的结合亲和力。(C)北京大学出版社.
Dimerization of HIV-I protease (HIV PR) monomers is an essential prerequisite for viral proteolytic activity and the subsequent generation of infectious virus particles. Disrupting dimerization of the enzyme can inhibit its activity. We have calculated the relative binding free energies between different dimers of the HIV protease using molecular dynamics and a continuum model, which we call MM/PBSA. We examined the dominant negative inhibition of the HIV PR by a mutated form of the protease and found relative dimerization free energies of homo- and hetero-dimerization consistent with experimental data. We also developed a rapid screening method, which was called the virtual mutagenesis method to consider other mutations which might stabilize non-wild-type heterodimers. Using this approach, we considered the mutations near the dimer interface which might cause dominant negative inhibition of the HIV PR. The rapid method we developed can be used in studying any ligand-protein and protein-protein interaction, in order to identify mutations that can enhance the binding affinities of the complex. (C) 2000 Academic Press.