REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Porto, Portugal.
J Phys Chem B. 2011 Jun 2;115(21):7045-57. doi: 10.1021/jp200075s. Epub 2011 May 5.
HIV-1 protease is a very attractive target for the development of new anti-HIV drugs and has been extensively studied over the past decades. In this study, we present a detailed atomic level characterization of the dimer interface in the enzyme HIV-1 protease through computational alanine scanning mutagenesis and molecular dynamics simulations. In addition to a full mapping of the amino acid residues present at the subunit interface, in terms of the corresponding energetic contribution for dimer formation and of their classification as hot spots, warm spots, and null spots, we trace a dynamic analysis of the subunit interacting and solvent accessible surface areas and of the most important hydrogen bonds between subunits. The results presented illustrate the high energetic importance for dimer formation of a small set of five amino acid residue pairs at the subunit interface-Leu5, Ile50, Arg87, Leu97, and Phe99-and provide important clues on the most important structural and energetic determinants for dimer formation. In addition, the results presented suggest several key targets at the subunit interface for the development of new molecules that aim to inhibit HIV-1 protease (PR) activity through blocking the formation of the fully active PR homodimeric form, providing important clues for drug design.
HIV-1 蛋白酶是开发新型抗 HIV 药物的极具吸引力的靶标，在过去几十年中得到了广泛的研究。在这项研究中，我们通过计算丙氨酸扫描突变和分子动力学模拟，对 HIV-1 蛋白酶酶中二聚体界面进行了详细的原子水平表征。除了全面绘制亚基界面上存在的氨基酸残基图谱，包括它们对二聚体形成的相应能量贡献以及它们作为热点、暖点和冷点的分类外，我们还对亚基相互作用和溶剂可及表面积以及亚基之间最重要的氢键进行了动态分析。所呈现的结果说明了在亚基界面上的一小部分五个氨基酸残基对（Leu5、Ile50、Arg87、Leu97 和 Phe99）对二聚体形成具有很高的能量重要性，并为二聚体形成的最重要的结构和能量决定因素提供了重要线索。此外，所呈现的结果表明在亚基界面上有几个关键靶点，可以开发新的分子，旨在通过阻止完全活性的 PR 同源二聚体形式的形成来抑制 HIV-1 蛋白酶（PR）活性，为药物设计提供了重要线索。
