Protein-specific force field derived from the fragment molecular orbital method can improve protein-ligand binding interactions

• Published in: Journal of computational chemistry 2013-05, Vol.34 (14), p.1251-1257
• Main Authors: Chang, Le, Ishikawa, Takeshi, Kuwata, Kazuo, Takada, Shoji
• Format: Article
• Language: English
• Subjects: ab initio molecular orbitals; Animals; Archaeal Proteins - chemistry; Archaeal Proteins - metabolism; Charged particles; Chickens; Computer Simulation; Correlation analysis; fragment molecular orbital; Halobacterium salinarum - chemistry; Halobacterium salinarum - metabolism; in silico screening; Ligands; Models, Molecular; molecular mechanics; Muramidase - chemistry; Muramidase - metabolism; Protein Binding; Proteins; restrained electrostatic potential; Simulation; Static Electricity; Thermodynamics
• ISSN: 0192-8651; 1096-987X
• DOI: 10.1002/jcc.23250

Accurate computational estimate of the protein–ligand binding affinity is of central importance in rational drug design. To improve accuracy of the molecular mechanics (MM) force field (FF) for protein–ligand simulations, we use a protein‐specific FF derived by the fragment molecular orbital (FMO) method and by the restrained electrostatic potential (RESP) method. Applying this FMO‐RESP method to two proteins, dodecin, and lysozyme, we found that protein‐specific partial charges tend to differ more significantly from the standard AMBER charges for isolated charged atoms. We did not see the dependence of partial charges on the secondary structure. Computing the binding affinities of dodecin with five ligands by MM PBSA protocol with the FMO‐RESP charge set as well as with the standard AMBER charges, we found that the former gives better correlation with experimental affinities than the latter. While, for lysozyme with five ligands, both charge sets gave similar and relatively accurate estimates of binding affinities. © 2013 Wiley Periodicals, Inc. Protein‐specific partial charge distribution on the protein surface can improve the ability of in silico protein‐ligand binding free energy calculations. The fragment molecular orbital method makes it possible to calculate the quantum mechanical electrostatic potential around the protein surface. Such electrostatic potential is used in the restrained electrostatic potential method to fit the partial charges on atoms in proteins.