A New Approach for Investigating the Molecular Recognition of Protein: Toward Structure-Based Drug Design Based on the 3D-RISM Theory.
A New Approach for Investigating the Molecular Recognition of Protein: Toward Structure-Based Drug Design Based on the 3D-RISM Theory.
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DOI：
10.1021/ct200358h
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发表时间：
2011-10
影响因子：
5.5
通讯作者：
Yasuomi Kiyota;N. Yoshida;F. Hirata
中科院分区：
文献类型：
--
作者：
Yasuomi Kiyota;N. Yoshida;F. Hirata
基于分子液体统计力学理论--三维参考相互作用位点模型（3D-RISM）理论，提出了一种研究蛋白质分子识别过程的新方法。求解常规3D-RISM方程的数值过程包括两个步骤。在第一步中，我们求解包含目标配体的溶剂混合物的普通RISM（或1D-RISM）方程，以获得溶液中分子之间的密度对相关函数（PCF）。然后，我们解决了3D-RISM方程的溶质-溶剂系统，找到三维密度分布函数（3D-DDF）的溶剂物种周围的蛋白质，使用PCF在第一步。该方法成功的关键是将目标配体视为“溶剂”物种之一。然而，成功是有限的，由于解决的1D-RISM方程的溶剂混合物，包括大的配体分子的困难。在本文中，我们提出了一种方法，它减轻了传统方法中对溶质尺寸的限制。在这种方法中，我们解决了溶质-溶质3D-RISM方程的蛋白质-配体系统，其中蛋白质和配体都被视为“溶质”在无限稀释。分别对蛋白质-溶剂和配体-溶剂系统求解3D和1D-RISM方程，以获得溶质周围溶剂的3D和1D-DDF，这是求解溶质-溶质3D-RISM方程所需的。该方法被应用到两个实际的和值得注意的例子有关药物设计。一种是黑腹果蝇中的气味结合蛋白，它与乙醇分子结合。另一种是磷脂酶A2，它被称为乙酰水杨酸或阿司匹林的受体。结果表明，该方法成功地再现了配体分子在实验测得的结合位点上的结合模式。
A new approach to investigate a molecular recognition process of protein is presented based on the three-dimensional reference interaction site model (3D-RISM) theory, a statistical mechanics theory of molecular liquids. Numerical procedure for solving the conventional 3D-RISM equation consists of two steps. In step 1, we solve ordinary RISM (or 1D-RISM) equations for a solvent mixture including target ligands in order to obtain the density pair correlation functions (PCF) among molecules in the solution. Then, we solve the 3D-RISM equation for a solute-solvent system to find three-dimensional density distribution functions (3D-DDF) of solvent species around a protein, using PCF obtained in the first step. A key to the success of the method was to regard a target ligand as one of "solvent" species. However, the success is limited due to a difficulty of solving the 1D-RISM equation for a solvent mixture, including large ligand molecules. In the present paper, we propose a method which eases the limitation concerning solute size in the conventional method. In this approach, we solve a solute-solute 3D-RISM equations for a protein-ligand system in which both proteins and ligands are regarded as "solutes" at infinite dilution. The 3D- and 1D-RISM equations are solved for protein-solvent and ligand-solvent systems, respectively, in order to obtain the 3D- and 1D-DDF of solvent around the solutes, which are required for solving the solute-solute 3D-RISM equation. The method is applied to two practical and noteworthy examples concerning pharmaceutical design. One is an odorant binding protein in the Drosophila melanogaster , which binds an ethanol molecule. The other is phospholipase A2, which is known as a receptor of acetylsalicylic acid or aspirin. The result indicates that the method successfully reproduces the binding mode of the ligand molecules in the binding sites measured by the experiments.