Stultz C M, Karplus M
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Proteins. 1999 Dec 1;37(4):512-29.
The Multiple Copy Simultaneous Search (MCSS) methodology for finding energetically favorable positions and orientations of small functional groups in a binding site is extended to include flexibility of the target. This makes possible the finding of novel minima not present in a fixed structure and so extends the diversity of inhibitors that can be constructed starting with the MCSS procedure. Quenched molecular dynamics is used to generate energetically favorable positions and orientations of the functional groups in the field of a flexible protein. The method is applied to the viral protein HIV-1 protease with methanol and methyl ammonium as a test case. If the protein is quenched with many copies of functional groups randomly distributed in the binding site, the resulting minima have ligand-protein interaction energies that are, on average, less favorable than those obtained with standard MCSS. This is a consequence of the renormalized potential function employed in the Locally Enhanced Sampling (LES) approximation. However, local optimizations of existing MCSS minima with a flexible protein results in lower energy minima in regions of the protein that are of particular interest. Their use in constructing a consensus protein model for ligand design is discussed.
用于在结合位点寻找小功能基团能量有利位置和取向的多拷贝同时搜索（MCSS）方法被扩展以纳入靶标的灵活性。这使得能够找到固定结构中不存在的新的极小值，从而扩展了从MCSS程序开始构建的抑制剂的多样性。采用猝灭分子动力学来生成柔性蛋白质场中功能基团的能量有利位置和取向。该方法以甲醇和甲基铵作为测试案例应用于病毒蛋白HIV-1蛋白酶。如果用许多随机分布在结合位点的功能基团拷贝对蛋白质进行猝灭，那么得到的极小值的配体-蛋白质相互作用能平均而言比用标准MCSS获得的更不理想。这是局部增强采样（LES）近似中采用的重正化势函数的结果。然而，用柔性蛋白质对现有MCSS极小值进行局部优化会在蛋白质特别感兴趣的区域产生能量更低的极小值。讨论了它们在构建用于配体设计的共有蛋白质模型中的用途。
