A combination of classical molecular dynamics (MD) simulation and ab initio fragment molecular orbital (FMO) calculation was applied to a complex formed between the main protease of the new coronavirus and the inhibitor N3 to calculate interactions within the complex while incorporating structural fluctuations mimicking physiological conditions. Namely, a statistical evaluation of interaction energies between N3 and amino acid residues was performed by processing a thousand of structure samples. It was found that relative importance of each residue is altered by the structural fluctuation. The MD-FMO combination should be promising to simulate protein related systems in a more realistic way.

Visualized IFIE results seen from chain-B of spike protein.

Visualization of the interfacial electrostatic complementarity (VIINEC) is a recently developed method for analyzing protein–protein interactions using electrostatic potential (ESP) calculated via the ab initio fragment molecular orbital method. In this Letter, the molecular interactions of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein with human angiotensin-converting enzyme 2 (ACE2) and B38 neutralizing antibody were examined as an illustrative application of VIINEC. The results of VIINEC revealed that the E484 of RBD has a role in making a local electrostatic complementary with ACE2 at the protein–protein interface, while it causes a considerable repulsive electrostatic interaction. Furthermore, the calculated ESP map at the interface of the RBD/B38 complex was significantly different from that of the RBD/ACE2 complex, which is discussed herein in association with the mechanism of the specificity of the antibody binding to the target protein.

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.

The SARS-CoV-2 virus initiates infection of human cells by recognizing the human angiotensin-converting enzyme 2 (ACE2) with the receptor binding domain (RBD) of the viral spike protein. Thus, the variant of concern (VOC) with mutations on RBD is of special interest. Here, we present a series of interaction analyses for the RBD–ACE2 complex of the wild-type (PDB ID: 6M0J) and those of B.1.1.7 (α), B.1.351 (β) and P.1 (γ) VOCs, based on the fragment molecular orbital (FMO) calculations. The results revealed that the RBD variants have a higher affinity for ACE2 than the wild type does.

In large biomolecular systems such as protein complexes, there are huge numbers of combinations of inter-residue interactions whose comprehensive analyses are often beyond the intuitive processing by researchers. Here we propose a computational method to allow for a systematic analysis of these interactions based on the fragment molecular orbital calculations, in which the inter-fragment interaction energies are comprehensively processed by the singular value decomposition. For a trimer complex of SARS-CoV-2 spike protein, three-body interactions among residues belonging to three chains are analyzed to elicit a small number of essential interaction modes or networks crucial for the structural stability of complex.

At the stage of SARS-CoV-2 infection to human cell, the spike protein consisting of three chains, A, B and C, with a total of 3.3 thousand residues plays the key role, and thus its nature have attracted considerable interests. Here, we report interaction analyses on the spike protein of both closed (PDB-ID: 6VXX) and open (6VYB) structures, based on large-scale fragment molecular orbital (FMO) calculations at the level of up to the fourth-order Møller-Plesset perturbation with singles, doubles and quadruples (MP4(SDQ)). Inter-chain interaction energies were evaluated for both structures, and mutual comparison indicated considerable losses of stabilization energies in the open structure, especially in the receptor binding domain (RBD) of chain-B. By two separate calculations for the RBD complexes with angiotensin converting enzyme 2 (ACE2) (6M0J) and B38 Fab antibody (7BZ5), it was found that this stabilization loss of RBD was partially compensated by the binding with ACE2 or antibody.

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