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.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.