Oral Presentation 10

日時： 2020 年 10 月 30 日 14:45-16:15
チャンネル： １

口頭発表１０『計算化学（分子計算）』
Computational Chemistry (Molecular Modeling)
座長： 石川 岳志 （鹿児島大学）
Takeshi Ishikawa (Kagoshima University)
O1-12"Advanced methods to predict properties of cyclic peptides: conformation analysis ofpeptides cyclized by non-amide bonds"
Kentaro Takai(Fujitsu Ltd.)
O1-13"Enhanced conformational sampling of cyclic peptide Cyclorasin by coupled
Nosé-Hoover equation"
Kei Moritsugu(Yokohama City University)
O1-14"Development status of ABINIT-MP program in 2020"
Yuji Mochizuki(Department of Chemistry & Research Center for Smart Molecules, Faculty ofScience, Rikkyo University & Institute of Industrial Science, University of Tokyo)
O1-15"Development of multiscale FMO-DPD simulations for molecular design"
Koji Okuwaki(Faculty of Science, Rikkyo University)

O1-12

Advanced methods to predict properties of cyclic peptides:
conformation analysis of peptides cyclized by non-amide bonds
Kentaro Takai 1

Sakiko Mori 1

takai.kentaro@fujitsu.com

mori.sakiko@fujitsu.com

Azuma Matsuura
1

Mutsuyo Wada 1

Akihiko Ueda 1

Atsushi Tomonaga
Seiji Fukui 1

Nozomu Kamiya 1

Fujitsu Ltd., 1-2-70 Konan, Minato-ku, Tokyo 108-0075, Japan

Keywords: Conformation analysis, Cyclic peptides
Drug discovery in middle sized molecules such as cyclic peptides is an attracting area as they
have higher selectivity compared to small molecules and higher membrane permeability compared
to antibodies. Since the properties depend on their conformation[1], we developed a “RingExpansion Method”[2] for the generation of cyclic glycine conformers and an addition method ofside chain conformers[3] to analyze the stable conformation exhaustively. In CBI annual meeting
2019, we reported these methods and calculation results for peptides cyclized by only the amidebond[4,5]. Recently, we expanded the scope of application to analyze conformations of peptides
cyclized by non-amide bonds.
Our new conformation analysis methods are as follows.
(i)
Generation of cyclic glycine conformers by “Ring Expansion Method”, and addition ofheavy atoms between N and CA atom in the main chain to generate non-amide bonds.
(ii) Substitution of a cyclic residue like the proline for a glycine residue and addition of aheavy atom whose position is uniquely determined (CB atom of the alanine or C atom ofthe N-methylated amide bond). These conformers are named “stem ring conformers”.
(iii) Addition of side chain conformers to the stem ring conformers.
We analyzed the conformation for the peptide (YDYPGDYCYLY) cyclized by non-amide bonds(PDB ID: 5KGN). In this study, we analyzed residues of the ring part (YDYPGDYC).
The analysis time was less than 2 hours
using 400 cores (Xeon E5-2660 (2.2 GHz)).
Theconformationsofseveral
stableconformers obtained were found to be similar
to that of the experimentally observed one. Thelowest RMSD between the PDB and obtained
conformations is 1.79 Å, here these conformers
are superposed on all heavy atoms (Figure 1).
When these are superposed on backbone atoms,
the lowest RMSD is 1.21 Å.
Our advanced methods achieved theconformation analysis of peptides cyclized by
Figure 1: The closest conformer (green line) tonot only the amide bond but also non-amide
the conformer reported in PDB (gray line). Thesebonds.
conformers are superposed on all heavy atoms.
[1] A. Whitty, M. Zhong, L. Viarengo, D. Beglov, D. R. Hall and S. Vajda, Drug Discovery Today,
21, 712 (2016).
[2] A. Tomonaga, H. Sugiyama and A. Ueda, WO2018/154789A1.
[3] A. Tomonaga, H. Sugiyama and A. Ueda, JP2019/179304A.
[4] S. Mori, et al., CBI annual meeting 2019, P1-27.
[5] K. Takai, et al., CBI annual meeting 2019, P1-28.

O1-13

Enhanced conformational sampling of cyclic peptide
Cyclorasin by coupled Nosé-Hoover equation

123

Kei Moritsugu 1

Koh Takeuchi 2

moritugu@yokohama-cu.ac.jp

koh-takeuchi@aist.go.jp

Yoshifumi Fukunishi 2

Ikuo Fukuda 3

y-fukunishi@aist.go.jp

ifukuda@sim.u-hyogo.ac.jp

Graduate School of Medical Life Science, Yokohama City University, Yokohama 230-0045,
Japan
National Institute of Advanced Industrial Science and Technology, Cellular and Molecular
Biotechnology Research Institute, Tokyo 135-0064, Japan
Graduate School of Simulation Studies, University of Hyogo, Kobe 650-0047, Japan

Keywords: cyclic peptide, Cyclorasin, membrane permeability, enhanced conformational sampling,
coupled Nosé-Hoover equation
The importance has been increasing in recent drug discovery to design cyclic peptides that havehigh affinity to target proteins for inhibition and high membrane permeability for drug delivery.
The affinity is estimated by simulating the fluctuation around the protein-peptide complexes andby calculating the associated binding free energies, whereas the membrane permeability should
rely on intrinsic flexibility of the cyclic peptides. To reveal the permeability in terms of atomistic
viewpoints, we have attempted to fully obtain the structural ensembles of our target cyclic peptides
by use of the coupled Nosé-Hoover equation (cNH) of our recent development [1,2].
The original Nosé-Hoover equation generates a canonical distribution at a predetermined statictemperature. In cNH, in contrast, a physical system is simulated at nonequilibrium temperature thatis fluctuating in a dynamic manner. This corresponds to a temperature replica exchange simulation
with continuous temperatures by adopting continuous time development using a single replica. The
dynamics are realized by coupling the physical system with a temperature system of small degrees
of freedom, both of which are described by the Nosé-Hoover method. The desired distribution of
the fluctuating temperature is achieved by the established formalism, allowing an enhanced
conformational sampling and a reconstruction of the canonical distribution for the physical system
at an arbitrary temperature.
Here, we chose Cyclorasin 9A5 [3] and a derivative as target cyclic peptide systems. Cyclorasin
inhibits Ras signaling by blocking Ras-effector protein interactions, which will have therapeutic
benefits in cancer patients. A derivative, 9A54, achieved higher affinity than 9A5 after smallmodifications, which, however, resulted in lower membrane permeability [3]. To explain thiscontroversial result from fully atomistic descriptions, we applied the cNH to sample the structuralensembles of both 9A5 and 9A54 in both explicit water and DMSO environments. The derived
structures indicated minor but significant changes in the structural dynamics via the modificationfrom 9A5 to 9A54, which is reasonably in agreement with the NMR experiment [4].
[1] I. Fukuda and K. Moritsugu, Phys. Rev. E (2016) 93: 033306.
[2] I. Fukuda and K. Moritsugu, J. Phys. A: Math. Theoret., in press.
[3] P. Upadhyaya, et al., Angew. Chem. Int. Ed. (2015) 54:7602.
[4] K. Takeuchi, et al., submitted.

O1-14Development status of ABINIT-MP program in 2020
Yuji Mochizuki 1,2 Kota Sakakura 3 Hiromasa Watanabe 4 Koji Okuwaki 1
fullmoon@rikkyo.ac.jp sakakura@j-focus.or.jp hi-watanabe@hpc.co.jp okuwaju@rikkyo.ac.jp

Kouichiro Kato 5 Naoki Watanabe 6 Yoshio Okiyama 7
kato.koichiro.957@m.kyushu-u.ac.jp naoki.watanabe@mizuho-ir.co.jp okiyama@nihs.go.jp

Kaori Fukuzawa 2,8 Tatsuya Nakano 7
k-fukuzawa@hoshi.ac.jp nakano@nihs.go.jp
12345678

Department of Chemistry & Research Center for Smart Molecules, Faculty of Science,
Rikkyo University, 3-34-1 Nishi-ikebukuro, Toshima-ku, Tokyo 171-8501, Japan
Institute of Industrial Science, University of Tokyo, 4 -6-1 Komaba, Meguro-ku, Tokyo
153-8505, JapanFoundation for Computational Science, 7-1-28 Minatojima Minamicho, Chuo-ku, Kobe,Hyogo 650-0047, Japan
HPC SYSTEMS Inc., Kaigan 3-9-15, Minato-ku, Tokyo 108-0022, Japan
Department of Applied Chemistry, Graduate School of Engineering & Center for MolecularSystems, Kyushu University, Nishi-ku, Fukuoka 819-0395, Japan
Mizuho Information & Research Institute Inc., 2-3 Kanda-nishiki-cho, Chiyoda-ku,
Tokyo 101-8443, Japan
Division of Medicinal Safety Science, National Institute of Health, 3 -25-26 Tonomachi
Kawasaki-ku, Kawasaki, Kanagawa 210-9501, Japan
School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara,
Shinagawa-Ku, Tokyo 142-8501, Japan

Keywords: Fragment molecular orbital, FMO, ABINIT-MP, Interaction energy analysis
We have been developing the ABINIT-MP program [1] for about 20 years, and this system has
been widely used in the fields of pharmaceutical chemistry and biophysics in Japan. The latest
distribution package is the Open Version 1 Revision 22 (hereafter denoted as Rev.22) as of June
2020. In Rev. 22, the calculation of PIEDA in ABINIT-MP [2] is greatly accelerated by improving
the loop structures; several bottlenecks of processing have been removed . Only the specified
region can be calculated at the MP2 or MP3 levels [3] in a multilayer FMO (MFMO) framework[4]. Additionally, the frozen-domain (FD) [5] is supported for partial geometry optimizations.
From April 2020, the trial usage of Fugaku has been provided for ABINIT-MP, and a series of FMO
calculations have been performed for several proteins related with COVID -19. With 3072 nodes ofFugaku, an FMO-MP3/cc-pVDZ job for a spike protein (consisting of 3.3 thousand amino acidresidues) could be completed in only 3.4 h.
In the presentation, we will show the features of Rev. 22 and some demonstrative results.
[Acknowledgment] This work was supported by the following projects; a social and scientific priority
issue #6 to be tackled by using post-K computer (Fugaku) operated by MEXT, Kaken-hi (16H04635),
AMED/BINDS (JP19an010101113) and Rikkyo SFR. The trial usage of Fugaku was conducted by
RIKEN R-CCS and MEXT under the special project against COVID-19 [6].
[1] Tanaka, S., et al., Electron-Correlated Fragment-Molecular-Orbital Calculations for
Biomolecular and Nano Systems, Phys. Chem. Chem. Phys., 16:10310-10344, 2014.
[2] Tsukamoto, T., et al., Implementation of Pair Interaction Energy Decomposition Analysis and Its
Applications to Protein-Ligand Systems, J. Comp. Chem. Jpn., 14:1-9, 2015.
[3] Mochizuki, Y., et al., Large-scale FMO-MP3 calculations on the surface proteins of influenzavirus, hemagglutinin (HA) and neuraminidase (NA), Chem. Phys. Lett., 493:346-352, 2010.
[4] Fedorov, D.G., et al., Multiconfiguration self-consistent-field theory based upon the fragment
molecular orbital method, J. Chem. Phys., 122:054108, 20005.
[5] Fedorov, D.G., et al., Geometry Optimization of the Active Site of a Large System with theFragment Molecular Orbital Method, J. Phys. Chem. Lett., 2:282-288, 2011.
[6] <https://www.r-ccs.riken.jp/library/topics/fugaku-coronavirus.html>.

O1-15Development of multiscale FMO-DPD simulations formolecular design
Koji okuwaki 1

Eiji Shinsho 2

Ruka Nishida 2okuwaki@rikkyo.ac.jp

m1813@hoshi.ac.jp

s162515@hoshi.ac.jp

Kaori Fukuzawa 2,3
k-fukuzawa@hoshi.ac.jp

12

3

4

Yuji Mochizuki 1,4
fullmoon@rikkyo.ac.jp

Department of Chemistry & Research Center for Smart Molecules, Faculty of Science, Rikkyo
University, 3-34-1 Nishi-ikebukuro, Toshima-ku, Tokyo 171-8501, Japan
School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara,
Shinagawa-Ku, Tokyo 142-8501, JapanGraduate School of Engineering, Tohoku University, 6 -6-04, Aramaki Aza Aoba Aoba-ku,Sendai, Miyagi 980-8579, Japan
Institute of Industrial Science, The University of Tokyo , 4-6-1 Komaba, Meguro-ku,Tokyo,
153-8505, Japan

Keywords: FMO-DPD, Multiscale simulation, Dissipative particle dynamics, Reverse map
In the fields of drug design or materials science, control of molecular structures at an atomistic
level is highly desired for the advancement of products, and pre-screening or understanding ofmolecular mechanism using computational chemistry has attracted much attention . In recent years,
the prediction of meso-scale structures formed by molecular aggregates is important issue because
meso-scale structure has a significant effect on various chemical and biological mechanisms. Inorder to predict meso-scale structures, simulations using coarse-grained models such as dissipative
molecular dynamics (DPD) [1] are commonly used for handling long time-scale and large systems.
The parameters that describe the interactions among particles are crucial for these simulations, andthey are generally closely related to the so-called χ parameters that correlated with the affinities
between components by the Flory-Huggins theory. However, it is well known that the evaluation ofa reliable set of χ parameters is a difficult problem, and thus values based on experimental data orempirical values are generally used in DPD simulation. The parameter-dependent applications
should have several limitations, and accurate evaluation of χ parameters is still a critical concern.
Our group has developed a new framework for calculating effective interaction parameters [2-4]between particles for meso-scale DPD simulations, based on nano-scale fragment molecular orbital(FMO) calculations [5] by using ABINIT-MP program [6]. In addition, the workflow of detailed
FMO analyses of fully atomistic structure generated from meso-scale structure using the reverse
map technology has been established recently. In other words, a series of the multiscale FMO-DPD
simulation systems have been completed. In this presentation, we outline the frameworks ofFMO-DPD and also the demonstrative applications [7-9].
[Acknowledgment] The present work was supported by MEXT as a social and scientific priority
issue #6 to be tackled by using post-K computer (FS2020), AMED-BINDS (JP20am0101113), andRikkyo SFR.
[1] R. Groot et al., J. Chem. Phys. 107 (1997) 4423. [2] C.F. Fan et al., Macromolecules 25(1992) 3667. [3] K. Okuwaki et al., J. Phys. Chem. B, 122 (2018) 338. [4] K. Okuwaki, et al., J.
Comput. Chem. Japan 17 (2018) 102. [5] D.G. Fedorov et al., CRC Press, Boca Raton, 2009. [6] S.
Tanaka et al., Phys. Chem. Chem. Phys. 16 (2014) 10310. [7] H. Doi et al., Chem. Phys. Lett. 684(2017) 427. [8] E. Shinsho et al., J. Comput. Chem. Japan 17 (2018) 172. [ 9] K. Okuwaki et al.,Appl. Phys. Express 13 (2020) 017002.