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

Abstract

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 (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 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.

Protein–ligand binding affinity prediction of cyclin‐dependent kinase‐2 inhibitors by dynamically averaged fragment molecular orbital‐based interaction energy

“…Fedorov et al 13 performed MD simulations with FMO calculations for two ligands bound to a Trp‐cage mini‐protein and systematically averaged the FMO‐based interaction energies to evaluate the protein–ligand binding energies. Hatada et al 14,15 also found the significance of structural fluctuations in the IFIE analysis on a complex system of SARS‐CoV‐2 main protease and N3 ligand. However, these studies have not addressed the ability of systematically averaged FMO‐based interaction energies to improve protein–ligand binding affinity predictions using a set of multiple candidate compounds.…”

“…Fedorov et al 13 performed MD simulations with FMO calculations for two ligands bound to a Trp-cage mini-protein and systematically averaged the FMO-based interaction energies to evaluate the protein-ligand binding energies. Hatada et al 14,15 also found the significance of structural fluctuations in the IFIE analysis on a complex system of SARS-CoV-2 main protease and N3 ligand.…”

“…The FMO‐based interaction energy can be obtained from a single protein–ligand complex structure (snapshot), such as an X‐ray crystal structure or a computationally modeled structure. However, previous studies 12–15 suggest that averaging the FMO‐based interaction energies over multiple structures is more reliable than considering only a single structure. Ishikawa et al 12 performed FMO calculations against 40 prion protein structures generated by molecular dynamics (MD) simulations and examined the influence of geometrical fluctuations on FMO calculations.…”

“…However, previous studies [12][13][14][15] suggest that averaging the FMObased interaction energies over multiple structures is more reliable than considering only a single structure. Ishikawa et al 12 performed FMO calculations against 40 prion protein structures generated by molecular dynamics (MD) simulations and examined the influence of geometrical fluctuations on FMO calculations.…”

Structural insights into the substrate‐binding site of main protease for the structure‐based COVID‐19 drug discovery

“…Then, for performing structural alignment, the intersection of residues involved in the formation of two antiparallel β-barrels between domains I and II for all monomers of M pro which contains 66 residues were selected based on "SHEET" records in the PDB files (See Table S2 for a list of residues contributing to the β-barrel structures). All M pro structures were aligned on the Cα atoms of the selected residues of a reference structure (6 LU7 chain A, the first released protein crystal structure for SARS-CoV-2 M pro in complex with a covalently bonded inhibitor N3, which has been analyzed and characterized in many experimental and computational studies 1,4,18,21,[41][42][43][44][45][46][47][48][49][50] ). The pairwise RMSD values for all above Cα atoms between every pair of the aligned protein structures did not exceed 0.43 Å, indicating that the antiparallel β-barrels arrangement is relatively stable and similar, and does not significantly change in the presence or absence of a ligand/inhibitor.…”