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

Abstract

By the splendid advance in computation power realized with Fugaku supercomputer, it has become possible to perform ab initio fragment molecular orbital (FMO) calculations for thousands of dynamical structures of a protein-ligand complex in a parallelized way. We have thus carried out the electron-correlated FMO calculations for a complex of the 3C-like (3CL) main protease (Mpro) of the new coronavirus (SARS-CoV-2) and its inhibitor N3 incorporating the structural fluctuations sampled by classical molecular dynamics (MD) simulation in hydrated condition. Along with a statistical evaluation of inter-fragment interaction energies (IFIEs) between the N3 ligand and surrounding amino-acid residues for a thousand of dynamical structure samples, we have applied in this study a novel approach based on the principal component analysis (PCA) and the singular value decomposition (SVD) to the analysis of IFIE data in order to extract the dynamically cooperative interactions between the ligand and residues. We have 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 dynamical manner through collective interactions formed by multiple residues, thus providing a new insight into structure-based drug discovery

Pateamine A mediates RNA sequence-selective translation repression by anchoring eIF4A and DDX3 to GNG motifs

“…calculations [50][51][52][53] based on the reported structure of human eIF4A1•DM-PatA•polypurine RNA 29 . For consistency with our experiments, we replaced DM-PatA with DMDA-PatA for the MD+FMO analysis 54 .…”

“…Then, FMO calculations were performed. The ABINIT-MP program (Tanaka et al 2014;Mochizuki et al 2021) was used for the FMO calculations; electron correlation effects were incorporated by second-order Møller-Plesset perturbation (MP2) theory, which was efficiently implemented in ABINIT-MP [76][77][78] . For the basis functions 52,53 , we used 6-31G*, a standard of FMO calculations.…”

“…The ABINIT-MP program (Tanaka et al 2014;Mochizuki et al 2021) was used for the FMO calculations; electron correlation effects were incorporated by second-order Møller-Plesset perturbation (MP2) theory, which was efficiently implemented in ABINIT-MP [76][77][78] . For the basis functions 52,53 , we used 6-31G*, a standard of FMO calculations. Subsequently, the average value and standard deviation of 40 structures of total IFIE with eIF4A and RNA for DMDA-PatA obtained using these FMO calculations were calculated for each pose.…”