A new approach for investigating the molecular recognition of protein: Toward structure-based drug design based on the 3D-RISM theory

Yasuomi Kiyota, Norio Yoshida, Fumio Hirata

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3803-3815
Number of pages13
JournalJournal of Chemical Theory and Computation
Volume7
Issue number11
DOIs
Publication statusPublished - Nov 8 2011
Externally publishedYes

Fingerprint

Molecular recognition
solutes
drugs
proteins
Proteins
Ligands
ligands
Pharmaceutical Preparations
Molecules
Aspirin
molecules
acetylsalicylic acid
Drosophila
Statistical mechanics
Phospholipases A2
Binding sites
statistical mechanics
Drug products
Probability density function
Dilution

All Science Journal Classification (ASJC) codes

  • Computer Science Applications
  • Physical and Theoretical Chemistry

Cite this

A new approach for investigating the molecular recognition of protein : Toward structure-based drug design based on the 3D-RISM theory. / Kiyota, Yasuomi; Yoshida, Norio; Hirata, Fumio.

In: Journal of Chemical Theory and Computation, Vol. 7, No. 11, 08.11.2011, p. 3803-3815.

Research output: Contribution to journalArticle

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