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Development of an Automated FMO Calculation Protocol to Construction of FMO Database

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Recent Advances of the Fragment Molecular Orbital Method

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Abstract

In recent years, inter-fragment interaction energy (IFIE) analyses based on the fragment molecular orbital (FMO) method have been widely used for drug design. The reason is that the IFIE analyses can quantify not only electrostatic interactions such as hydrogen bonds but also dispersion forces such as CH/π interactions difficult to evaluate with classical molecular mechanics (MM). On the other hand, because preparing an input structure for the FMO calculation requires a lot of complicated preprocessing, including complementation of missing atoms and structure optimization, it is difficult to process a large number of structures. In this study, an automated FMO calculation protocol (Auto-FMO protocol) was developed to calculate huge numbers of protein and ligand complexes, such as drug discovery targets, by an ab initio FMO method. The protocol performs structure preparation as preprocessing, submission of FMO processing, and analysis of FMO results as post-processing. Optionally, quantum mechanics/molecular mechanics (QM/MM) optimization of complex structures, conformational searches of ligand structures in solution, and molecular mechanics Poisson–Boltzmann or generalized Born surface area (MM-PBSA/GBSA) calculations can also be carried out. To demonstrate the usefulness of the Auto-FMO protocol, we first compared the ligand-binding interaction energies of 20 estrogen receptor α (ERα) and 70 p38 MAP kinase datasets prepared by the Auto-FMO protocol with those prepared manually. In most cases, the interaction energies showed reasonable agreement between both preparations. Based on such technology, we constructed the FMO database (FMODB; https://drugdesign.riken.jp/FMODB/) published in February 2019, consisting of quantum chemical calculation results with the FMO method. FMODB currently contains thousands of FMO calculation data for hundreds of proteins mostly processed by the Auto-FMO protocol. By constructing FMODB and its web interface, even researchers unfamiliar with quantum mechanics (QM) calculations can analyze inter- and intra-molecular interactions of target proteins. Furthermore, accumulation of FMO data is expected to lead to accurate prediction of ligand activities and construction of QM-based force fields by using machine learning and artificial intelligence (AI). This chapter was reprinted and adapted with permission from Watanabe et al. CBI J. 2019, 58, 5–18. Copyright 2019 Chem-Bio Informatics Society [38].

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Acknowledgements

The authors thank Dr. Teruki Honma, Dr. Kikuko Kamisaka, Mr. Shunpei Nagase, Dr. Kaori Fukuzawa, and Prof. Shigenori Tanaka for their collaborators. The authors would like to thank Dr. Kazumi Tsuda and Mr. Daisuke Murayama at Science & Technology Systems, Inc., for supporting the development of the automated FMO calculation protocol. This research was conducted as part of the activity of the FMO drug design consortium (FMODD). The FMO calculations were performed on the K computer (project IDs: hp150160, hp160103, hp170183, and hp180147). For QM/MM optimizations, the supercomputer HOKUSAI (RIKEN Advanced Center for Computing and Communications) was used. PIEDA calculations were performed with the MIZUHO/BioStation software package. This research was partially supported by the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED under Grant Number JP18am0101113. The authors acknowledge JSPS KAKENHI Grant Number JP18K06619 and JST PRESTO Grant Number JPMJPR18GD.

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Authors and Affiliations

  1. RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045, Kanagawa, Japan

    Chiduru Watanabe & Daisuke Takaya

  2. JST, PRESTO, 4-1-8, Honcho, Kawaguchi, 332-0012, Saitama, Japan

    Chiduru Watanabe

  3. Education Center On Computational Science and Engineering, Kobe University, 7-1-48, Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Hyogo, Japan

    Hirofumi Watanabe

  4. Division of Medicinal Safety Science, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, 210-9501, Kanagawa, Japan

    Yoshio Okiyama

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  1. Chiduru Watanabe
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  2. Hirofumi Watanabe
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  3. Yoshio Okiyama
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  4. Daisuke Takaya
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Correspondence to Chiduru Watanabe .

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Editors and Affiliations

  1. Department of Chemistry, Faculty of Science, Rikkyo University, Tokyo, Japan

    Yuji Mochizuki

  2. Graduate School of System Informatics, Kobe University, Kobe, Japan

    Shigenori Tanaka

  3. School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Tokyo, Japan

    Kaori Fukuzawa

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Watanabe, C., Watanabe, H., Okiyama, Y., Takaya, D. (2021). Development of an Automated FMO Calculation Protocol to Construction of FMO Database. In: Mochizuki, Y., Tanaka, S., Fukuzawa, K. (eds) Recent Advances of the Fragment Molecular Orbital Method. Springer, Singapore. https://doi.org/10.1007/978-981-15-9235-5_9

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