10月28日（木）Zoom ブレイクアウトルーム
口頭発表５＜口頭発表５＞『計算化学（分子計算）／計算化学（分子認識）／分子ロボティクス』
座長：佐藤 佑介（東北大学）、髙岡 雄司（ダッソー・システムズ㈱）
O5-01

O5-02
O5-03
O5-04

O5-05
O5-06

Hiroki Ozono (Kagoshima University)"Visualization of the interfacial electrostatic complementarity: A
method for analysis of protein-protein interaction based on fragment
molecular orbital method"
Suyong Re (National Institutes of Biomedical Innovation, Health andNutrition)"gREST prediction of substrate bindings to stereoselective enzymes"
Ikuo Kurisaki (Kobe Univ., Grad. Sch. Sys. Inform.)"Prediction of Disassembly Pathway of Multimeric Protein Complex
by Hybrid Monte Carlo Simulations"
Ken Komiya (Japan Agency for Marine-Earth Science andTechnology)"Investigation of the optimal arrangement of state sequences for
efficient operation of a DNA state machine"
Gregory Gutmann (Tokyo Institute of Technology)"Toward Hands-on Molecular Design and Testing Enabled byInteractive VR Simulation"
Hirotaka Kondo (Kansai University, Organization for Research andDevelopment of Innovative Science and Technology)"Development of a prototype VR AFM manipulation system emulated
by a dispensing machine"

O5-1

Visualization of the interfacial electrostatic
complementarity: A method for analysis of protein-protein
interaction based on fragment molecular orbital method
Hiroki Ozono 1

k8340102@kadai.jp

1Takeshi Ishikawa 1

ishi@cb.kagoshima-u.ac.jp

Department of Chemistry, Biotechnology, and Chemical Engineering, Graduate School ofScience and Engineering, Kagoshima University, 1-21-40 Korimoto, Kagoshima, Kagoshima
890-0065, Japan

Keywords: E lectrostatic complementarity, Protein–Protein interaction, Fragment molecularorbital method, PAICS

Protein–protein interactions (PPIs) are extensively investigated due to their important roles innumerous biological processes, resulting in that PPIs are now spotlighted as a new target of drug
discovery. Additionally, a detailed understanding of PPIs is essential for the design of antibodies usedfor various research purposes and/or therapeutic applications based on their high affinity and target
specificity. Therefore, the importance of computational approaches to provide physicochemical insight
into PPIs has increased. To accurately evaluate the charge transfer and polarization caused by theprotein–protein bindings, quantum chemical approaches are desired.
Very recently, we developed a method for analyzing the PPI based on the ab initio fragmentmolecular orbital (FMO) method [1,2], which is called visualization of the interfacial electrostaticcomplementarity (VIINEC). In this method, electrostatic interaction at the protein–protein interface
can be visually analyzed using the electron density (EDN) and electrostatic potential (ESP) obtained
from the FMO calculation of the complex. VIINEC was implemented in PAICS (one of the FMO
program packages) [3,4], and several calculations showed that VIINEC quantitatively evaluates theelectronic induced fit due to the complex formation by comparison with the ESPs calculated in theisolate condition. The degree of the contribution of each amino acid to the electrostatic
complementarity between the proteins was also quantitatively calculated. In addition, a part of themechanism of the specificity of the target recognition of anti-bodies could be addressed.
Here we report the methodological aspects of VIINEC and illustrative calculations for the complexesof programmed cell death-1 (PD-1) with its ligand or anti-bodies targeting PD-1, which demonstrates
the potential of VIINEC in life-science researches.

[1] T. Ishikawa, A novel method for analysis of the electrostatic complementarity ofprotein-protein interaction based on fragment molecular orbital method, Chem. Phys. Lett., 761(2020) 138103.
[2] H. Ozono, T. Ishikawa, Visualization of the interfacial electrostatic complementarity: A method
for analysis of protein – protein interaction based on ab initio quantum chemical calculations, J.
Chem. Theory Comput. in press.
[3] T. Ishikawa, et al., Theoretical study of the prion protein based on the fragment molecularorbital method, J. Comput. Chem., 30 (2009) 2594.
[4] http://www.paics.net/

O5-2

gREST prediction of substrate bindings to stereoselectiveenzymes
Suyong Re 1,2

Naoki Kato 3,4suyongre@nibiohn.go.jp

naoki.kato@setusnan.ac.jp

Shingo Nagano 5snagano@tottori-u.ac.jp

123

4

5

67

Keisuke Fujiyama 5
keisuke.fujiyama@riken.jp

Yuji Sugita 2,6,7
sugita@riken.jp

Artificial Intelligence Center for Health and Biomedical Research National Institutes ofBiomedical Innovation, Health, and Nutrition 7-6-8, Saito-Asagi, Ibaraki, Osaka, 567-0085,
JapanLaboratory for Biomolecular Function Simulation, RIKEN Center for Biosystems Dynamics
Research, 6-7-1 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
Faculty of Agriculture, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka,573-0101, Japan
Natural Product Biosynthesis Research Unit, RIKEN Center for Sustainable Resource Science,
2-1 Hirosawa, Wako, Saitama 351-0198, Japan
Department of Chemistry and Biotechnology Graduate School of Engineering, Tottori
University, 4-101 Koyama-cho Minami, Tottori, 680-8550, Japan
Theoretical Molecular Science Laboratory, RIKEN Cluster for Pioneering Research, 2-1
Hirosawa, Wako, Saitama, 351-0198, Japan
Computational Biophysics Research Team, RIKEN Center for Computational Science, 6-7-1
Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan

Keywords: Protein-ligand binding, Molecular dynamics simulation, generalized replica-exchangewith solute tempering
Molecular Dynamics (MD) simulations are increasingly used to predict protein-ligand bindings.
Advances in enhanced sampling algorithms enable us to perform ms-scale simulations, rapidlyraising the predictive power. Here, we apply the generalized replica-exchange with solutetempering method, gREST [1], which is a generalization of REST/REST2 [2], for the prediction ofsubstrate bindings of stereoselective enzymes, Fsa2 and Phm7 [3]. Two enzymes catalyze [4+2]cycloadditions to form enantiomeric products. The gREST simulations extensively sampled
possible binding poses otherwise elusive in conventional simulations, predicted the binding
models consistent with the site-directed mutagenesis experiment. Intriguingly, the substrate boundto each of enzymes exhibits largely different flexibility, suggesting the distinctive mechanism
behind these stereoselective reactions.
[1] Kamiya, M.; Sugita, Y. J. Chem. Phys. 2018, 149, 072304.
[2] Wang, L. et al. J. Phys. Chem. B 2011, 115, 9431–9438. Moors, S. L. C. et al. J. Chem. Theory
Comput. 2011, 7, 231–237. Terakawa, T. et al. J. Comput. Chem. 2011, 32, 1228–1234.
[3] Fujiyama, K.; Kato, N.; Re, S.; Kinugasa, K.; Watanabe, K.; Takita, R.; Nogawa, T.; Hino, T.;
Osada, H.; Sugita, Y.; Takahashi, S.; Nagano, S. Angew. Chem. Int. Ed. 2021,
DOI:anie.202106186.

O5-3

Prediction of Disassembly Pathway of Multimeric Protein
Complex by Hybrid Monte Carlo Simulations

1Ikuo KURISAKI 1

Shigenori TANAKA 1

kurisaki1@bear.kobe-u.ac.jp

tanaka2@kobe-u.ac.jp

Kobe Univ., Grad. Sch. Sys. Inform., 1-1 Rokko-dai, Kobe, Hyogo, 657-8501, Japan

Keywords: Molecular Recognition, Molecular Dynamics, Mass Spectrometry, Hybrid Monte Carlo
Physicochemical characterization of multimeric biomacromolecule assembly and disassembly
processes is a milestone for understanding biological phenomena at the molecular level. Massspectroscopy (MS) and structural bioinformatics (SB) techniques have become feasible to identify
subcomplexes involved in such processes [1,2]. This kind of information can be an initial andcritical step toward calculations of free energy profiles of the processes, although the atomistic
information that MS and SB studies give is not satisfactory for the purpose.
To combine information derived from MS and SB studies with conventional free energy
calculation protocols, we designed a new reaction pathway sampling method by employing a
hybrid Monte Carlo/Molecular Dynamics (hMC/MD) scheme [3]. Rare events such as associativeand dissociative molecular diffusions are accelerated in each MD phase by employing Steered MD(SMD) method. A reaction coordinate of the SMD simulation is randomly selected from thecandidates of subunit pairs. Meanwhile, a configuration generated by enhanced sampling is
rejected with a certain probability by Metropolis algorithm in MC phase to circumvent selection ofsubcomplex configurations anomalously deformed by the usage of the SMD simulations.
First, we applied it to simulating the disassembly process of serum amyloid P component (SAP)
pentamer, a ring-shaped homomeric protein complex. The disassembly process we simulated isconsistent with that of the earlier MS and SB studies for SAP subcomplex species. Furthermore,
we observed a novel dissociation event, the ring -opening reaction of SAP pentamer, where one of
the five subunit interaction interfaces is broken. This ring-open form emerges in advance to theother set of subcomplexes, the trimer plus dimer and tetramer plus monomer.
Next, employing free energy calculation combined with the hMC/MD reaction pathway
trajectories, we obtained experimentally testable observations on (1) reaction time of thering-opening reaction and (2) importance of Asp42 and Lys117 for stable formation of SAPoligomer.
We would also present the latest progress of the hMC/MD scheme, modifications to effi ciently
predict the disassembly process of heteromeric protein complexes.
[1] Hall Z. et al. The role of salt bridges, charge density, and subunit flexibility in determining
disassembly routes of protein complexes, Structure 2013, 21, 1325-1337.
[2] Petersen L.X et al. Modeling the assembly order of multimeric heteroprotein complex. PLoS
Comput. Biol. 2018, No. e1005937.
[3] Kurisaki I.; Tanaka S. Reaction pathway sampling and free-energy analyses for multimeric
protein complex disassembly by employing hybrid configurational bias Monte Carlo/molecular
dynamics simulation, ACS Omega 2021, 6, 4749-4758.

O5-4

Investigation of the optimal arrangement of state
sequences for efficient operation of a DNA state machine
Ken Komiya 1
komiyak@jamstec.go.jp

Satoshi Kobayashi 2
kobayashi.satoshi@uec.ac.jp

Masayuki Yamamura 3
my@c.titech.ac.jp

1

2
3

4

John A. Rose 4
jarose@apu.ac.jp

Japan Agency for Marine-Earth Science and Technology, 2-15 Natsushima-cho, Yokosuka,Kanagawa, 237-0061, JapanThe University of Electro-Communications, 1-5-1 Chofugaoka, Chofu, Tokyo, 182-8585 JapanTokyo Institute of Technology, J2-51, 4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa,226-8503 Japan
Ritsumeikan Asia Pacific University, 1-1 Jumonjibaru, Beppu, Oita, 874-8556 Japan

Keywords: DNA state machine, hairpin structure, statistical thermodynamic model
Whiplash PCR (WPCR) is a unique reaction system, which implements successive statetransitions according to a computational program encoded by each DNA molecule, in the form ofpairs of state sequences and intervening stopper sequences [1]. By iterating hairpin structureformation and DNA polymerase extension, WPCR allows the program-parallel computation to
perform various types of information processing, including solution to a graph problem [2].
However, WPCR requires very high temperature conditions due to its characteristic reaction design
utilizing the sub-stable hairpin formation. We formerly revealed that the competitive formation of
the sub-stable hairpin structure as the target structure leads to the requirement of high temperature
conditions [3, 4]. In this work, we investigated the effect of changing the arrangement and lengthof state sequences on the efficiency of the target hairpin structure formation. The present results
would help to improve the design of WPCR, by reducing the problematic thermophilic property ofthe DNA state machine with the aid of statistical thermodynamic model simulation. In addition, we
report a preliminary investigation of the proposed design via a biochemical experiment.
[1] Sakamoto, K.; Kiga, D.; Komiya, K.; Gouzu, H.; Yokoyama, S.; Ikeda, S.; Sugiyama, H.;Hagiya M. State Transitions by Molecules, BioSystems, 1999, 52, 81-91.
[2] Komiya, K.; Sakamoto, K.; Kameda, A.; Yamamoto, M.; Ohuchi, A.; Kiga, D.; Yokoyama, S.;
Hagiya M. DNA polymerase programmed with a hairpin DNA incorporates amultiple-instruction architecture into molecular computing, BioSystems, 2006, 83, 18-25.
[3] Komiya, K.; Yamamura M.; Rose, J. A. Quantitative design and experimental validation for asingle-molecule DNA nanodevice transformable among three structural states, Nucleic Acids
Research, 2010, 38(13), 4539-4546.
[4] Rose, J. A.; Komiya, K.; Kobayashi, S. Engineering multistate DNA molecules: a tunable
thermal band-pass filter, Micro & Nano Letters, 2016, 11(10), 595-601.

O5-5

Toward Hands-on Molecular Design and Testing Enabled byInteractive VR Simulation
Gutmann Gregory Spence1,3
gutmann.g.aa@m.titech.ac.jp

Hirotada Kondo2
kondo@vraide.jp

Zhang Yuhui1,3zhang.y.av@m.titech.ac.jp

Akihiko Konagaya3

konagaya@molecular-robot.com

Tokyo Institute of Technology, School of Computing
Kansai University, Chemistry and Materials Engineering
3
Molecular Robot Research Institute, Co., Ltd.
12Keywords: Molecular Robotics, Interactive VR Simulation, Hands-on Molecular Design and Testing
Works in molecular and nanoscale research and engineering continue to be more common as the desire forbetter drugs, nanoscale machines, and materials are constant. However, the process of designing at thenano-scale is complicated by the fact that we cannot see or interact with target molecular objects directly
due to their sizes. As a solution to this, we are proposing a method that will enable hands-on design andtesting of nanoscale structures and systems. We are proposing an interactive VR simulation system thatenables users to dive into the molecular world and interact with biomolecules at the nanoscale, as well as
simulate with conventional MD equations. It is feasible that we could load atomic structures, probe theirdynamics in VR, reposition them in solvent, simulate with conventional equations, and then probe thedynamics again to see the changes in the system. This would enable researchers to quickly set up
experiments and obtain results in a hands-on manner, in contrast to time-consuming data entry, or relying
on testing large sets of random initial conditions to find possible solutions.
By combining an interactive VR environment and molecular dynamics simulation, we believe ourproposed work will be able to offer greater insight into the molecular world and enable a greater degree ofcontrol over the setup of virtual experiments, enabling users to analyze and understand the molecular worldin greater detail as it floats in front of them in VR.

[1] Gregory Gutmann, Ryuzo Azuma, Akihiko Konagaya: A Virtual Reality Computational Platform
Dedicated for the Emergence of Global Dynamics in a Massive Swarm of Objects, J. of the Imaging
Society of Japan, 2018, 57(6), 647-653.

O5-6

Development of a Prototype VR AFM Manipulation System
Emulated by a Dispensing Machine
Hirotada Kondo1

Gutmann Gregory Spence2

kondo@vraide.jp

ggutmann13@jcu.edu

Akinori Kuzuya3,4

Akihiko Konagaya4

kuzuya@kansai-u.ac.jp

konagaya@molecular-robot.com

1

Organization for Research and Development of Innovative Science and Technology, Kansai University
School of Computing, Tokyo Institute of Technology
2
Department of Chemistry and Materials Engineering, Kansai University
3
Molecular Robot Research Institute, Co., Ltd.
1

Keywords: Molecular Robotics, VR Simulation, Atomic Force Microscope, DNA origami

Molecular manipulation using a microscope probe tip is one of promising approaches to be applied not only
for observation but also for selective molecular capture and microfabrication. In order to solve difficulties
in operations of molecular manipulation using microscope imaging, we propose a VR system for interactive
and intuitive molecular operations. The system consists of a virtual Atomic Force Microscope (VAFM) as
a molecular-sized robot arm, virtual molecules, and a remote machine operation interface. Our virtual nanomechanical DNA origami device (VDNA pliers) attached on the VAFM can bind a single target molecule
selectively, so that it works as a gripper of the robot arm.
The remote machine operation interface enables us to manipulate a real experimental equipment from theVR system. Currently, we can intuitively manipulate virtual AFM, which is a dispensing machine thatemulates a real AFM, with hand movements and observe the movement. This is a first step toward ananoscale manipulator that can intuitively manipulate target molecules with DNA pliers attached to the endof an AFM cantilever operated from the VR system.
[1] Gregory Gutmann, Ryuzo Azuma, Akihiko Konagaya: A Virtual Reality Computational Platform
Dedicated for the Emergence of Global Dynamics in a Massive Swarm of Objects, J. of the Imaging
Society of Japan, 2018, 57(6), 647-653.
[2] Akinori Kuzuya, Yusuke Sakai, Takahiro Yamazaki, Yan Xu, Makoto Komiyama: NanomechanicalDNA origami 'single-molecule beacons' directly imaged by atomic force microscopy, Nature Commun.,
2011, 2, 449.