Dynamic Cooperativity of Ligand-Residue Interactions Evaluated with the Fragment Molecular Orbital Method.

Autor: Tanaka S; Graduate School of System Informatics, Department of Computational Science, Kobe University, 1-1 Rokkodai, Nada-ku, Kobe 657-8501, Japan., Tokutomi S; Graduate School of System Informatics, Department of Computational Science, Kobe University, 1-1 Rokkodai, Nada-ku, Kobe 657-8501, Japan., Hatada R; Department of Chemistry and Research Center for Smart Molecules, Faculty of Science, Rikkyo University, 3-34-1 Nishi-ikebukuro, Toshima-ku, Tokyo 171-8501, Japan., Okuwaki K; Department of Chemistry and Research Center for Smart Molecules, Faculty of Science, Rikkyo University, 3-34-1 Nishi-ikebukuro, Toshima-ku, Tokyo 171-8501, Japan., Akisawa K; Department of Chemistry and Research Center for Smart Molecules, Faculty of Science, Rikkyo University, 3-34-1 Nishi-ikebukuro, Toshima-ku, Tokyo 171-8501, Japan., Fukuzawa K; School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.; Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University, 6-6-11 Aoba, Aramaki, Aoba-ku, Sendai 980-8579, Japan.; Institute of Industrial Science, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan., Komeiji Y; Biomedical Research Institute, AIST, Tsukuba Central 6, Tsukuba, Ibaraki 305-8566, Japan., Okiyama Y; Division of Medicinal Safety Science, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 201-9501, Japan., Mochizuki Y; Department of Chemistry and Research Center for Smart Molecules, Faculty of Science, Rikkyo University, 3-34-1 Nishi-ikebukuro, Toshima-ku, Tokyo 171-8501, Japan.; Institute of Industrial Science, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan.
Jazyk: angličtina
Zdroj: The journal of physical chemistry. B [J Phys Chem B] 2021 Jun 24; Vol. 125 (24), pp. 6501-6512. Date of Electronic Publication: 2021 Jun 14.
DOI: 10.1021/acs.jpcb.1c03043
Abstrakt: By the splendid advance in computation power realized with the Fugaku supercomputer, it has become possible to perform ab initio fragment molecular orbital (FMO) calculations for thousands of dynamic structures of protein-ligand complexes in a parallel way. We thus carried out electron-correlated FMO calculations for a complex of the 3C-like (3CL) main protease (M pro ) of the new coronavirus (SARS-CoV-2) and its inhibitor N3 incorporating the structural fluctuations sampled by classical molecular dynamics (MD) simulation in hydrated conditions. Along with a statistical evaluation of the interfragment interaction energies (IFIEs) between the N3 ligand and the surrounding amino-acid residues for 1000 dynamic structure samples, in this study we applied a novel approach based on principal component analysis (PCA) and singular value decomposition (SVD) to the analysis of IFIE data in order to extract the dynamically cooperative interactions between the ligand and the residues. We found that the relative importance of each residue is modified via the structural fluctuations and that the ligand is bound in the pharmacophore in a dynamic manner through collective interactions formed by multiple residues, thus providing new insight into structure-based drug discovery.
Databáze: MEDLINE
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