Hot spot profiles of SARS-CoV-2 and human ACE2 receptor protein protein interaction obtained by density functional tight binding fragment molecular orbital method

Lim, Hyun Jeong; Baek, Ayoung; Kim, Jongwan; Kim, Min Sung; Liu, Jiaxin; Nam, Ky Youb; Yoon, Jeong Hyeok; No, Kyoung Tai

doi:10.1038/s41598-020-73820-8

Cited by 60 publications

(45 citation statements)

References 32 publications

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“…The fragment molecular orbital method was developed by Kitaura et al in 1999 [34]. In recent years, FMO has been increasingly used in new drug designs based on accurate energy calculations, especially in protein-ligand and protein-protein interaction analysis [35][36][37][38][39][40][41]. In order to investigate PPI, a 3-dimensional scattered pair interaction energy (FMO/3D-SPIE) analysis was introduced to sort vital interactions with the FMO method, and it efficiently correlated the results with experimental site-directed mutagenesis results [36].…”

Section: Introductionmentioning

confidence: 99%

Hot Spot Analysis of YAP-TEAD Protein-Protein Interaction Using the Fragment Molecular Orbital Method and Its Application for Inhibitor Discovery

Kim

Lim

Moon³

et al. 2021

Cancers

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The Hippo pathway is an important signaling pathway modulating growth control and cancer cell proliferation. Dysregulation of the Hippo pathway is a common feature of several types of cancer cells. The modulation of the interaction between yes-associated protein (YAP) and transcriptional enhancer associated domain (TEAD) in the Hippo pathway is considered an attractive target for cancer therapeutic development, although the inhibition of PPI is a challenging task. In order to investigate the hot spots of the YAP and TEAD interacting complex, an ab initio Fragment Molecular Orbital (FMO) method was introduced. With the hot spots, pharmacophores for the inhibitor design were constructed, then virtual screening was performed to an in-house library. Next, we performed molecular docking simulations and FMO calculations for screening results to study the binding modes and affinities between PPI inhibitors and TEAD. As a result of the virtual screening, three compounds were selected as virtual hit compounds. In order to confirm their biological activities, cellular (luciferase activity, proximity ligation assay and wound healing assay in A375 cells, qRT-PCR in HEK 293T cells) and biophysical assays (surface plasmon resonance assays) were performed. Based on the findings of the study, we propose a novel PPI inhibitor BY03 and demonstrate a profitable strategy to analyze YAP–TEAD PPI and discover novel PPI inhibitors.

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Section: Introductionmentioning

confidence: 99%

Hot Spot Analysis of YAP-TEAD Protein-Protein Interaction Using the Fragment Molecular Orbital Method and Its Application for Inhibitor Discovery

Kim

Lim

Moon³

et al. 2021

Cancers

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“…Moreover, the essential hot spots of the 15 common amino acid residues on ACE2 and the 28 common residues on SARS S-proteins identified in the current study are partially in agreement with hot spots on ACE2 identified by Lim et al via FMO calculations using the self-consistent charge density-functional tightbinding method with third-order expansion using semiempirical dispersion (DFTB3/D) method. 13 Lim et al showed two sizable hot spot regions, where several hot spots were assembled 13 . Their results were almost consistent with our results, showing that the common hot spots between ACE2 and S-protein were as follows: The first hot spot region included Q24ACE2, A25ACE2, F28ACE2, D30ACE2, K31ACE2, E35ACE2, and Y83ACE2, which interacted with K417Spike, L455Spike, S477Spike, E484Spike, F486Spike, N487Spike, Y489Spike, and Q493Spike in the SARS-CoV-2.…”

Section: Hot Spot Analysis Of S-proteinmentioning

confidence: 99%

“…Lim et al has shown two large hot spot regions from FMO-based interaction analysis of ACE2 and S-proteins of the SARS-CoV-2. 13 Since the hot spots of S-protein with the several neutralizing antibodies of the SARS-CoV coincided with the 2 nd hot spot region, the authors speculated that the 2 nd hot spot region was crucial for drug design against the SARS-CoV-2. However, our results suggest that all key hot spots for molecular recognition between the SARS-CoV-2 S protein and ACE2 may play a significant role in the design of neutralizing antibodies.…”

Section: Fmo-based Epitope Analysismentioning

confidence: 99%

“…3,[6][7][8][9] Analyses of molecular recognition hots spots between the SARS-CoV-2 S-protein and ACE2 were conducted by several computational simulations, including electrostatic potential, 10,11 molecular mechanics (MM)-based interaction energy analysis with classical force field, 12 and quantum mechanics (QM)-based interaction energy analysis with evaluation of semiempirical dispersion energy. 13 Molecular dynamic (MD) simulations for the complex formed by the S-protein and ACE2 were conducted to better understand their association. [14][15][16] Approaches for drug/neutralizing antibody design targeting S-protein have been reported, such as a de novo design peptide inhibitors for SRAS-CoV-2 17 , a virtual screening of antiviral compounds for the SARS-CoV-2 18 and sequence-based epitope analysis for the SARS-CoV-2, among others 19 .…”

Section: Introductionmentioning

confidence: 99%

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Molecular Recognition of SARS-CoV-2 Spike Glycoprotein: Quantum Chemical Hot Spot and Epitope Analyses

Watanabe

Okiyama²,

Tanaka³

et al. 2020

Preprint

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<div>Due to the COVID-19 pandemic, researchers have attempted to identify complex structures of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (S-protein) with angiotensin-converting enzyme 2 (ACE2) or a blocking antibody. However, the molecular recognition mechanism - critical information for drug and antibody design - has not been fully clarified at the amino acid residue level. Elucidating such a microscopic mechanism in detail requires a more accurate molecular interpretation that includes quantum mechanics to quantitatively evaluate hydrogen bonds, XH/π interactions (X = N, O, and C), and salt bridges. In this study, we applied the fragment molecular orbital (FMO) method to characterize the SARS-CoV-2 S-protein binding interactions with not only ACE2 but also the B38 Fab antibody involved in ACE2-inhibitory binding. By analyzing FMO-based interaction energies along a wide range of binding inter-faces carefully, we identified amino acid residues critical for molecular recognition between S-protein and ACE2 or B38 Fab antibody. Importantly, hydrophobic residues that attribute to weak interactions such as CH-O and XH/π interactions, as well as polar residues that construct conspicuous hydrogen bonds, play important roles in molecular recognition and binding ability. Moreover, through these FMO-based analyses, we also clarified novel hot spots and epitopes that had been overlooked in previous studies by structural and molecular mechanical approaches. Altogether, these hot spots/epitopes identified between S-protein and ACE2/B38 Fab antibody may provide useful information for future anti-body design and small or medium drug design against the SARS-CoV-2. </div><div><br></div>

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“… 17 , 18 As for QM calculation, the fragment molecular orbital (FMO) method 19 , 20 is one of the methods that can treat the entire protein with uniform accuracy. The FMO calculation for several specific SARS-CoV-2-related proteins, such as the S protein, 21 − 25 Mpro, 26 − 30 and RdRp, 31 have been performed using the ABINIT-MP program 32 , 33 and the GAMESS program. 34 − 36 The ABINIT-MP program used in this paper is capable of performing precise electron correlation calculations at the MP4 (SDQ) level for S proteins of up to 3300 residues using the Fugaku supercomputer.…”

Section: Introductionmentioning

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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Hot spot profiles of SARS-CoV-2 and human ACE2 receptor protein protein interaction obtained by density functional tight binding fragment molecular orbital method

Cited by 60 publications

References 32 publications

Hot Spot Analysis of YAP-TEAD Protein-Protein Interaction Using the Fragment Molecular Orbital Method and Its Application for Inhibitor Discovery

Hot Spot Analysis of YAP-TEAD Protein-Protein Interaction Using the Fragment Molecular Orbital Method and Its Application for Inhibitor Discovery

Molecular Recognition of SARS-CoV-2 Spike Glycoprotein: Quantum Chemical Hot Spot and Epitope Analyses

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

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