The worldwide spread of COVID-19
(new coronavirus found in 2019)
is an emergent issue to be tackled. In fact, a great amount of works
in various fields have been made in a rather short period. Here, we
report a fragment molecular orbital (FMO) based interaction analysis
on a complex between the SARS-CoV-2 main protease (Mpro) and its peptide-like
inhibitor N3 (PDB ID: 6LU7). The target inhibitor molecule was segmented into
five fragments in order to capture site specific interactions with
amino acid residues of the protease. The interaction energies were
decomposed into several contributions, and then the characteristics
of hydrogen bonding and dispersion stabilization were made clear.
Furthermore, the hydration effect was incorporated by the Poisson–Boltzmann
(PB) scheme. From the present FMO study, His41, His163, His164, and
Glu166 were found to be the most important amino acid residues of
Mpro in interacting with the inhibitor, mainly due to hydrogen bonding.
A guideline for optimizations of the inhibitor molecule was suggested
as well based on the FMO analysis.
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.
SARS-CoV-2 is the causative agent of coronavirus (known as COVID-19), the virus causing
the current pandemic. There are ongoing research studies to develop effective
therapeutics and vaccines against COVID-19 using various methods and many results have
been published. The structure-based drug design of SARS-CoV-2-related proteins is
promising, however, reliable information regarding the structural and intra- and
intermolecular interactions is required. We have conducted studies based on the fragment
molecular orbital (FMO) method for calculating the electronic structures of protein
complexes and analyzing their quantitative molecular interactions. This enables us to
extensively analyze the molecular interactions in residues or functional group units
acting inside the protein complexes. Such precise interaction data are available in the
FMO database (FMODB) (
). Since April 2020, we have performed
several FMO calculations on the structures of SARS-CoV-2-related proteins registered in
the Protein Data Bank. We have published the results of 681 structures, including three
structural proteins and 11 nonstructural proteins, on the COVID-19 special page (as of
June 8, 2021). In this paper, we describe the entire COVID-19 special page of the FMODB
and discuss the calculation results for various proteins. These data not only aid the
interpretation of experimentally determined structures but also the understanding of
protein functions, which is useful for rational drug design for COVID-19.
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