1
Special feature of COVID-19 in FMODB: Fragment molecular orbital
calculations and interaction energy analysis of SARS-CoV-2 related
proteins
Kaori Fukuzawa
a, b*
, Koichiro Kato
c,d*
, Chiduru Watanabe
e,f*
, Yusuke Kawashima
a
, Yuma Handa
a
, Ami
Yamamoto
a
, Kazuki Watanabe
g,h
, Tatsuya Ohyama
e,i
, Kikuko Kamisaka
e
, Daisuke Takaya
e
, Teruki
Honma
e*
a. Department of Physical Chemistry, School of Pharmacy and Pharmaceutical Sciences, Hoshi
University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
b. Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University,
6-6-11 Aoba, Aramaki, Aoba-ku, Sendai 980-8579, Japan
c. Department of Applied Chemistry, Graduate School of Engineering, Kyushu University, 744
Motooka, Nishi-ku, Fukuoka 819-0395, Japan
d. Center for Molecular Systems (CMS), Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-
0395, Japan
e. RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama,
Kanagawa, 230-0045, Japan
f. JST PRESTO, 4-1-8, Honcho, Kawaguchi, Saitama 332-0012, Japan
g. Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita City,
Osaka 565-0871, Japan
h. Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba
260-8675, Japan
i. Frontier Institute for Biomolecular Engineering Research (FIBER), Konan University, 7-1-20,
Minatojima-minamimachi, Chuo-ku, Kobe 650–0047, Japan
*Corresponding author. Email: k-fukuzawa@hoshi.ac.jp (K. Fukuzawa),
kato.koichiro.957@m.kyushu-u.ac.jp (K. Kato), chiduru.watanabe@riken.jp (C. Watanabe),
honma.teruki@riken.jp (T. Honma)
Abstract
SARS-CoV-2 is the causative agent of coronavirus(known as COVID-19), the virus causing
the current pandemic. there are ongoing researches 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,
2
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 structure 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 protein complexes. Such precise interaction
data are available in the FMO database (FMODB) (https://drugdesign.riken.jp/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 eleven 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 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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1. Introduction
The COVID-19 pandemic has been ongoing since its declaration by WHO in March 2020,
and as of June 8, 2021, it had killed 3,718,944 people and infected 172 million people
worldwide
1
. COVID-19 has had a devastating impact on global health and economic activities,
and the loss of social infrastructure due to urban lockdown has reached unprecedented levels,
with no signs of abatement. To fight against COVID-19, there is a need to understand the
causative virus, SARS-CoV-2, and develop effective vaccines and therapies. Consequently,
structural analyses of SARS-CoV-2 related proteins have been rapidly conducted and are
available worldwide in the Protein Data Bank (PDB)
2
. In addition to experimental structures,
researchers worldwide collate model structures, MD simulation results, and bioinformatics
data and made them available as their data resources
3
. The PDB Japan (PDBj)
4, 5
has
categorized PDB data of SARS-CoV-2 related proteins into “All entries,” “Representative
entries,” and “Latest entries” on the COVID-19 special page, and 1,277 structures are
available as of June 8, 2021. Viral proteins include four structural proteins (SP) that form
virus particles and 16 nonstructural proteins (NSP) intracellularly produced after infecting
human cells. The structures of three SP and thirteen NSP have already been clarified by cryo-
electron microscopy (Cryo-EM), X-ray, and NMR. Though these structural data are very
useful information for developing therapeutic agents, there is a need to precisely calculate and
clarify how these viral proteins interact with each other and when candidate therapeutic
compounds bind strongly to the proteins.
We have performed several fragment molecular orbital (FMO)
6, 7
-based quantum chemical
calculations on the entire structure of SARS-CoV-2 related proteins, focusing on the
representative entries of PDBj, and all the results have been published in the FMO database
(FMODB)
8
9
since April 2020. In FMODB, all FMO calculation results can be downloaded
and molecular interaction analysis can be performed through the web interface and BioStation
Viewer software
10
. In this paper, we describe FMO calculation results (681 structures as of
June 8, 2021) available on the COVID-19 special page of FMODB.
2. Method
2.1 Molecular Modeling
We performed FMO calculations for 681 protein structures, mainly from the representative
entries published on the COVID-19 special page of PDBj, to reveal their precise interaction
energies. MOE
11
was employed for molecular modeling, and structural refinement was
performed according to the resolution of the registered structures following the procedure
shown in Figure 1. Here, missing atoms in the PDB structure are complemented, and
appropriate structural optimization is performed. The level of structural optimization is
4
changed according to the experimental method and its resolution, but for some data,
exceptions are made, such as performing structural optimization for nonhydrogen atoms, even
when the resolution is less than 2.0.
5
Figure 1. Sequence of workflow from downloading PDB structure to FMODB registration
2.2 FMO Calculation
The basic fragmentation method for FMO calculations is as follows: proteins are
fragmented into amino acid residue units, nucleic acids are fragmented into backbone and
base units, and ligands are fragmented into one or several fragments
12
. Quantum chemical
calculations were performed at the theoretical level of FMO2-MP2/6-31G*
13, 14
to calculate
the total energy (𝐸
total
), atomic charge, and interfragment interaction energy (IFIE; ∆𝐸
𝐼𝐽
).
𝐸
total
= ∑𝐸
𝐼
′
𝐼
+ ∑∆𝐸
𝐼𝐽
𝐼>J
(
1
)
IFIE can be further decomposed into four energy components, including electrostatic (ES),
exchange repulsion (EX), charge transfer with higher-order terms (CT + mix), and dispersion
(DI) terms. This is known as the pair interaction energy decomposition analysis (PIEDA)
15
16
, and it is expressed as follows:
∆𝐸
𝐼𝐽
= ∆𝐸
𝐼𝐽
ES
+ ∆𝐸
𝐼𝐽
EX
+ ∆𝐸
𝐼𝐽
CT+mix
+ ∆𝐸
𝐼𝐽
DI
(
2
)
PIEDA is vital in applying the FMO method to drug discovery because it gives information
about the characteristics of the interaction, in addition to their magnitude (stable or unstable).
For interpreting PIEDA, please refer to FMO books
7
17
and the original reference
15
. Hydrogen
bonding is mainly detected as the stabilization energy for the ES and CT + mix terms, and
hydrophobic type of interactions, such as CH/ and − are mainly detected as the
stabilization energy for the DI term.
Among the data registered in FMODB, for entries for which the binding energy can be
defined, such as protein–ligand, protein–protein, and protein–RNA, the binding energy is
calculated from the sum of IFIEs. The binding energy between molecules A and B (ΔE
AB
) is
expressed as follows:
∆𝐸
𝐴𝐵
= ∑∆𝐸
𝐼𝐽
𝐼∈𝐴
𝐽∈𝐵
(
3
)
All calculations in FMODB were performed using ABINIT-MP
18
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, a FMO calculation
software. We used supercomputers, including TSUBAME3.0 at Tokyo Institute of
Technology, Oakforest-PACS at JCAHPC, and FUGAKU and HOKUSAI at RIKEN.
