Life science
Drug development, Life science, Antibody design, Database

Elucidation of antibody recognition mechanism
by quantum chemical calculations
Quantum Life Science and Bioinformatics, Graduate School of Pharmaceutical Sciences
Professor Kaori Fukuzawa
https://researchmap.jp/kaori.fukuzawa

Life science

Abstract
For the design of antibody drugs, it is important to understandthe interaction between antigens and antibodies. The FMO method
evaluates the interaction energy of each amino acid residue quantitatively based on the three-dimensional structure of protein complexes, and identifies important residues to provide clues for drug
discovery. For example, the interaction analysis of the complex
structure of spike protein and antibody with 12 types of antibodies
for the novel coronavirus showed a good correlation with the experimental activity value (IC50) and succeeded in identifying 9 residues
that could be epitopes as antibody recognition sites (Fig.1).

antibodies. The same approach can be applied to various drug
discovery modalities, and is useful for rational and efficient molecular design that is effective not only for conventional small molecule
drug discovery, but also for the design of new modalities such as
nucleic acid drugs and lipid nanoparticles.

▍ Background & Results
Drug discovery and development is also becoming increasinglydigitalized. The FMO method enables large-scale quantum chemical calculations by treating macromolecules such as proteins as
fragments. It also enables quantitative evaluation of inter-fragmentinteraction energies, which can be used for molecular design
based on an understanding of molecular interactions. The FMO
Drug Design Consortium is working to develop the FMO method
as a practical drug discovery method by using the supercomputer“Fugaku” (project number: No. hp220143). The FMO database(FMODB) is being constructed and made available to the public. In
novel coronaviruses, comprehensive FMO calculations have been
performed on the complex structures of spike proteins and antibodies. In the example of the receptor binding domain (RBD) of the
spike protein and 12 antibodies, a good correlation was obtained
between the antigen-antibody binding energy and IC50 (R2=0.540).
The antibody recognition site is similar to the human ACE2 receptor recognition site, and in all complexes, nine specific residues
on the RBD surface contribute to the stabilization of the interaction
with the antibody (Fig. 1). A similar approach can be used in theanalysis of mutant strains, indicating that the FMO method is usefulfor epitope prediction. Comprehensive FMO calculations for other novel coronavirus-related proteins are also available from theFMODB (Figure 2). We are currently performing FMO calculations
for various antigen-antibody complexes published in the Protein
Data Bank and accumulating basic data for prediction of antibody
modification by integrating FMO and AI.

▍ Significance of the research and Future perspective

Figure 1. Interaction between spike protein and antibody

Figure 2. Top page of the FMO Database (FMODB) (left) and the number of registered structures (right)

Today, computational science and AI are beginning to be usedeverywhere to reduce the enormous cost and time required for
drug discovery and development. Our research is expected toelucidate the molecular recognition mechanism of antibodies related to diseases through precise calculations based on quantum
mechanics, and to be useful for the efficient design of modified

P a t e n t
Watanabe, Kazuki; Watanabe, Chiduru; Honma, Teruki et al. Intermolecular Interaction Analyses on SARS-CoV-2 Spike Protein Receptor Binding Domain
and Human Angiotensin-Converting Enzyme 2 Receptor-Blocking Antibody/Peptide Using Fragment Molecular Orbital Calculation. J. Phys. Chem. Lett.,
2021, 12, 4059–4066. doi: 10.1021/acs.jpclett.1c00663
Fukuzawa, Kaori; Kato, Koichiro; Watanabe, Chiduru et al. Special Feature of COVID-19 in FMODB: Fragment Molecular Orbital Calculations andT r e a t i s e Interaction Energy Analysis of SARS-CoV-2 Related Proteins. J. Chem. Info. Model. 2021, 61, 4594-4612. doi: 10.1021/acs.jcim.1c00694
Fukuzawa, Kaori; Tanaka, Shigenori. Fragment Molecular Orbital Calculations for Biomolecules. Curr. Opin. Struct. Biol, 2022, 72, 127-134.
doi: 10.1016/j.sbi.2021.08.010
Takaya, Daisuke; Watanabe, Chiduru; Nagase, Shunpei et al. FMODB: The world’s first database of quantum mechanical calculation forbiomacromolecules based on the fragment molecular orbital method. J. Chem. Info. Model., 2021, 61, 777-794. doi: 10.1021/acs.jcim.0c01062https://fmodd.jp/
URL
https://drugdesign.riken.jp/FMODB/K e y w o r d In silico drug discovery, antibody design, computational life science, fragment molecular orbital (FMO) method, supercomputer Fugaku