Statistical interaction analyses between SARS-CoV-2 main protease and inhibitor N3 by combining molecular dynamics simulation and fragment molecular orbital calculation

Hatada, Ryo; Okuwaki, Koji; Akisawa, Kazuki; Mochizuki, Yuji; Handa, Yuma; Fukuzawa, Kaori; Komeiji, Yuto; Okiyama, Yoshio; Tanaka, Shigenori

doi:10.35848/1882-0786/abdac6

Cited by 18 publications

(45 citation statements)

References 57 publications

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“…In addition, statistical interaction analyses using FMO calculations for several sampled structures from classical MD calculations have been reported. 27 Among the COVID-19-related proteins in the FMODB, the Mpro has the highest number of registered structures.…”

Section: Resultsmentioning

confidence: 99%

Special Features of COVID-19 in the FMODB: Fragment Molecular Orbital Calculations and Interaction Energy Analysis of SARS-CoV-2-Related Proteins

Fukuzawa

Kato

Watanabe

et al. 2021

J. Chem. Inf. Model.

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SARS-CoV-2 is the causative agent of coronavirus (known as COVID-19), the virus causing the current pandemic. There are ongoing research studies 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, 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 structures 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 the protein complexes. Such precise interaction data are available in the FMO database (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 11 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 the 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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Section: Resultsmentioning

confidence: 99%

Special Features of COVID-19 in the FMODB: Fragment Molecular Orbital Calculations and Interaction Energy Analysis of SARS-CoV-2-Related Proteins

Fukuzawa

Kato

Watanabe

et al. 2021

J. Chem. Inf. Model.

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“…For the complex of Mpro and N3 inhibitor (PDBID: 6LU7), FMO calculations were performed and registered in FMODB by Hatada et al 32 when the PDB structure was published (FMODBID: R1GK8). In addition, statistical interaction analyses using FMO calculations for several sampled structures from classical MD calculations have been reported 33 . Among the COVID-19-related proteins in FMODB, Mpro has the highest number of registered structures.…”

Section: Main Protease (Nsp5)mentioning

confidence: 99%

Special feature of COVID-19 in FMODB: Fragment molecular orbital calculations and interaction energy analysis of SARS-CoV-2 related proteins

Fukuzawa

Kato

Watanabe

et al. 2021

Preprint

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SARS-CoV-2 is the causative agent of coronavirus(known as , 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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“…24, the structural fluctuation effect (which should be essential in physiological condition) was not incorporated there because we performed only a single-structure FMO calculation with the 6LU7 crystal structure data. 14) Therefore, we 34) subsequently carried out the same FMO approach for the M pro -N3 complex again, but using a thousand of structure samples generated by classical MD simulation. This demanding task was firstly realized through large capacity computing with the novel use of a massively parallel computing resource of Fugaku supercomputer 35) at RIKEN in Kobe.…”

Section: Introductionmentioning

confidence: 99%

“…Our present problem is what we can do using these dynamical interaction data with quantum chemical accuracy. In addition to our earlier study 34) mainly concerning the dynamical average and fluctuation of protein-ligand IFIEs, we here employ two statistical techniques of data analysis, principal component analysis (PCA) and singular value decomposition (SVD), [36][37][38] to elicit the collective dynamics of interactions between a ligand molecule and surrounding aminoacid residues. Through these novel approaches, we anticipate that cooperative interactions between the ligand and multiple residues can be described dynamically to represent the specific binding modes of ligand molecule in the pharmacophore.…”

Section: Introductionmentioning

confidence: 99%

Dynamical Cooperativity of Ligand-Residue Interactions Evaluated with the Fragment Molecular Orbital Method

Tanaka

Tokutomi²,

Hatada³

et al. 2021

Preprint

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By the splendid advance in computation power realized with Fugaku supercomputer, it has become possible to perform ab initio fragment molecular orbital (FMO) calculations for thousands of dynamical structures of a protein-ligand complex in a parallelized way. We have thus carried out the electron-correlated FMO calculations for a complex of the 3C-like (3CL) main protease (Mpro) of the new coronavirus (SARS-CoV-2) and its inhibitor N3 incorporating the structural fluctuations sampled by classical molecular dynamics (MD) simulation in hydrated condition. Along with a statistical evaluation of inter-fragment interaction energies (IFIEs) between the N3 ligand and surrounding amino-acid residues for a thousand of dynamical structure samples, we have applied in this study a novel approach based on the principal component analysis (PCA) and the singular value decomposition (SVD) to the analysis of IFIE data in order to extract the dynamically cooperative interactions between the ligand and residues. We have found that the relative importance of each residue is modified via the structural fluctuations and that the ligand is bound in the pharmacophore in a dynamical manner through collective interactions formed by multiple residues, thus providing a new insight into structure-based drug discovery

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Statistical interaction analyses between SARS-CoV-2 main protease and inhibitor N3 by combining molecular dynamics simulation and fragment molecular orbital calculation

Cited by 18 publications

References 57 publications

Special Features of COVID-19 in the FMODB: Fragment Molecular Orbital Calculations and Interaction Energy Analysis of SARS-CoV-2-Related Proteins

Special Features of COVID-19 in the FMODB: Fragment Molecular Orbital Calculations and Interaction Energy Analysis of SARS-CoV-2-Related Proteins

Special feature of COVID-19 in FMODB: Fragment molecular orbital calculations and interaction energy analysis of SARS-CoV-2 related proteins

Dynamical Cooperativity of Ligand-Residue Interactions Evaluated with the Fragment Molecular Orbital Method

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