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Article ; Online: Full-Length Computational Model of the SARS-CoV-2 Spike Protein and Its Implications for a Viral Membrane Fusion Mechanism.

Nishima, Wataru / Kulik, Marta

2021 Volume 13, Issue 6

Abstract: The SARS-CoV-2 virus has now become one of the greatest causes of infectious death and morbidity since the 1918 flu pandemic. Substantial and unprecedented progress has been made in the elucidation of the viral infection process in a short time; however, ...

Abstract	The SARS-CoV-2 virus has now become one of the greatest causes of infectious death and morbidity since the 1918 flu pandemic. Substantial and unprecedented progress has been made in the elucidation of the viral infection process in a short time; however, our understanding of the structure-function dynamics of the spike protein during the membrane fusion process and viral uptake remains incomplete. Employing computational approaches, we use full-length structural models of the SARS-CoV-2 spike protein integrating Cryo-EM images and biophysical properties, which fill the gaps in our understanding. We propose a membrane fusion model incorporating structural transitions associated with the proteolytic processing of the spike protein, which initiates and regulates a series of events to facilitate membrane fusion and viral genome uptake. The membrane fusion mechanism highlights the notable role of the S1 subunit and eventual mature spike protein uptake through the host membrane. Our comprehensive view accounts for distinct neutralizing antibody binding effects targeting the spike protein and the enhanced infectivity of the SARS-CoV-2 variant.
MeSH term(s)	Computer Simulation ; Cryoelectron Microscopy/methods ; Humans ; Membrane Fusion ; Proteolysis ; SARS-CoV-2/chemistry ; SARS-CoV-2/physiology ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/metabolism ; Virus Internalization
Chemical Substances	Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2021-06-11
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v13061126
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Full-Length Computational Model of the SARS-CoV-2 Spike Protein and Its Implications for a Viral Membrane Fusion Mechanism

Nishima, Wataru / Kulik, Marta

Viruses. 2021 June 11, v. 13, no. 6

2021

Abstract	The SARS-CoV-2 virus has now become one of the greatest causes of infectious death and morbidity since the 1918 flu pandemic. Substantial and unprecedented progress has been made in the elucidation of the viral infection process in a short time; however, our understanding of the structure–function dynamics of the spike protein during the membrane fusion process and viral uptake remains incomplete. Employing computational approaches, we use full-length structural models of the SARS-CoV-2 spike protein integrating Cryo-EM images and biophysical properties, which fill the gaps in our understanding. We propose a membrane fusion model incorporating structural transitions associated with the proteolytic processing of the spike protein, which initiates and regulates a series of events to facilitate membrane fusion and viral genome uptake. The membrane fusion mechanism highlights the notable role of the S1 subunit and eventual mature spike protein uptake through the host membrane. Our comprehensive view accounts for distinct neutralizing antibody binding effects targeting the spike protein and the enhanced infectivity of the SARS-CoV-2 variant.
Keywords	Severe acute respiratory syndrome coronavirus 2 ; bioinformatics ; death ; influenza ; membrane fusion ; models ; morbidity ; pandemic ; pathogenicity ; proteolysis ; viral genome ; viruses
Language	English
Dates of publication	2021-0611
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2516098-9
ISSN	1999-4915
ISSN	1999-4915
DOI	10.3390/v13061126
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Article ; Online: Hyper-swivel head domain motions are required for complete mRNA-tRNA translocation and ribosome resetting.

Nishima, Wataru / Girodat, Dylan / Holm, Mikael / Rundlet, Emily J / Alejo, Jose L / Fischer, Kara / Blanchard, Scott C / Sanbonmatsu, Karissa Y

Nucleic acids research

2022 Volume 50, Issue 14, Page(s) 8302–8320

Abstract: Translocation of messenger RNA (mRNA) and transfer RNA (tRNA) substrates through the ribosome during protein synthesis, an exemplar of directional molecular movement in biology, entails a complex interplay of conformational, compositional, and chemical ... ...

Abstract	Translocation of messenger RNA (mRNA) and transfer RNA (tRNA) substrates through the ribosome during protein synthesis, an exemplar of directional molecular movement in biology, entails a complex interplay of conformational, compositional, and chemical changes. The molecular determinants of early translocation steps have been investigated rigorously. However, the elements enabling the ribosome to complete translocation and reset for subsequent protein synthesis reactions remain poorly understood. Here, we have combined molecular simulations with single-molecule fluorescence resonance energy transfer imaging to gain insights into the rate-limiting events of the translocation mechanism. We find that diffusive motions of the ribosomal small subunit head domain to hyper-swivelled positions, governed by universally conserved rRNA, can maneuver the mRNA and tRNAs to their fully translocated positions. Subsequent engagement of peptidyl-tRNA and disengagement of deacyl-tRNA from mRNA, within their respective small subunit binding sites, facilitate the ribosome resetting mechanism after translocation has occurred to enable protein synthesis to resume.
MeSH term(s)	Peptide Elongation Factor G/metabolism ; Protein Biosynthesis ; RNA, Messenger/chemistry ; RNA, Transfer/metabolism ; Ribosomes/metabolism
Chemical Substances	Peptide Elongation Factor G ; RNA, Messenger ; RNA, Transfer (9014-25-9)
Language	English
Publishing date	2022-07-09
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkac597
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Article ; Online: Correction to "Mosaic of Water Orientation Structures at a Neutral Zwitterionic Lipid/Water Interface Revealed by Molecular Dynamics Simulations".

Re, Suyong / Nishima, Wataru / Tahara, Tahei / Sugita, Yuji

The journal of physical chemistry letters

2015 Volume 6, Issue 1, Page(s) 195

Language	English
Publishing date	2015-01-02
Publishing country	United States
Document type	Published Erratum
ISSN	1948-7185
ISSN (online)	1948-7185
DOI	10.1021/jz502676e
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Article ; Online: Mechanisms for Two-Step Proton Transfer Reactions in the Outward-Facing Form of MATE Transporter.

Nishima, Wataru / Mizukami, Wataru / Tanaka, Yoshiki / Ishitani, Ryuichiro / Nureki, Osamu / Sugita, Yuji

Biophysical journal

2016 Volume 110, Issue 6, Page(s) 1346–1354

Abstract: Bacterial pathogens or cancer cells can acquire multidrug resistance, which causes serious clinical problems. In cells with multidrug resistance, various drugs or antibiotics are extruded across the cell membrane by multidrug transporters. The multidrug ... ...

Abstract	Bacterial pathogens or cancer cells can acquire multidrug resistance, which causes serious clinical problems. In cells with multidrug resistance, various drugs or antibiotics are extruded across the cell membrane by multidrug transporters. The multidrug and toxic compound extrusion (MATE) transporter is one of the five families of multidrug transporters. MATE from Pyrococcus furiosus uses H(+) to transport a substrate from the cytoplasm to the outside of a cell. Crystal structures of MATE from P. furiosus provide essential information on the relevant H(+)-binding sites (D41 and D184). Hybrid quantum mechanical/molecular mechanical simulations and continuum electrostatic calculations on the crystal structures predict that D41 is protonated in one structure (Straight) and, both D41 and D184 protonated in another (Bent). All-atom molecular dynamics simulations suggest a dynamic equilibrium between the protonation states of the two aspartic acids and that the protonation state affects hydration in the substrate binding cavity and lipid intrusion in the cleft between the N- and C-lobes. This hypothesis is examined in more detail by quantum mechanical/molecular mechanical calculations on snapshots taken from the molecular dynamics trajectories. We find the possibility of two proton transfer (PT) reactions in Straight: the 1st PT takes place between side-chains D41 and D184 through a transient formation of low-barrier hydrogen bonds and the 2nd through another H(+) from the headgroup of a lipid that intrudes into the cleft resulting in a doubly protonated (both D41 and D184) state. The 1st PT affects the local hydrogen bond network and hydration in the N-lobe cavity, which would impinge on the substrate-binding affinity. The 2nd PT would drive the conformational change from Straight to Bent. This model may be applicable to several prokaryotic H(+)-coupled MATE multidrug transporters with the relevant aspartic acids.
MeSH term(s)	Archaeal Proteins/chemistry ; Archaeal Proteins/metabolism ; Binding Sites ; Crystallography, X-Ray ; Hydrogen Bonding ; Hydrophobic and Hydrophilic Interactions ; Lipids/chemistry ; Models, Biological ; Molecular Dynamics Simulation ; Protons ; Pyrococcus furiosus/metabolism
Chemical Substances	Archaeal Proteins ; Lipids ; Protons
Language	English
Publishing date	2016-03-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2016.01.027
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Zs.A 235: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 2: Show issues

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Article ; Online: Mosaic of Water Orientation Structures at a Neutral Zwitterionic Lipid/Water Interface Revealed by Molecular Dynamics Simulations.

Re, Suyong / Nishima, Wataru / Tahara, Tahei / Sugita, Yuji

The journal of physical chemistry letters

2014 Volume 5, Issue 24, Page(s) 4343–4348

Abstract: Ordering of water structures near the surface of biological membranes has been recently extensively studied using interface-selective techniques like vibrational sum frequency generation (VSFG) spectroscopy. The detailed structures of interface water ... ...

Abstract	Ordering of water structures near the surface of biological membranes has been recently extensively studied using interface-selective techniques like vibrational sum frequency generation (VSFG) spectroscopy. The detailed structures of interface water have emerged for charged lipids, but those for neutral zwitterionic lipids remain obscure. We analyze an all-atom molecular dynamics (MD) trajectory of a hydrated 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine bilayer to characterize the orientation of interface waters in different chemical environments. The structure and dynamics of interfacial waters strongly depend on both their vertical position along the bilayer normal as well as vicinal lipid charged groups. Water orientation in the vicinity of phosphate groups is opposite to that around choline groups. The results are consistent with observed VSFG spectra and demonstrate that a mosaic of water orientation structures exists on the surface of a neutral zwitterionic phospholipid bilayer, reflecting rapid water exchange and the influence of local chemical environments.
Language	English
Publishing date	2014-12-18
Publishing country	United States
Document type	Journal Article
ISSN	1948-7185
ISSN (online)	1948-7185
DOI	10.1021/jz502299m
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Article ; Online: Backbone Circularization Coupled with Optimization of Connecting Segment in Effectively Improving the Stability of Granulocyte-Colony Stimulating Factor.

Miyafusa, Takamitsu / Shibuya, Risa / Nishima, Wataru / Ohara, Rie / Yoshida, Chuya / Honda, Shinya

ACS chemical biology

2017 Volume 12, Issue 10, Page(s) 2690–2696

Abstract: Backbone circularization of protein is a powerful method to improve its structural stability. In this paper, we presumed that a tight connection leads to much higher stability. Therefore, we designed circularized variants of a granulocyte-colony ... ...

Abstract	Backbone circularization of protein is a powerful method to improve its structural stability. In this paper, we presumed that a tight connection leads to much higher stability. Therefore, we designed circularized variants of a granulocyte-colony stimulating factor (G-CSF) with a structurally optimized terminal connection. To estimate the appropriate length of the connection, we surveyed the Protein Data Bank to find local structures as a model for the connecting segment. We set the library of local structures composed of "helix-loop-helix," subsequently selected entries similar to the G-CSF terminus, and finally sorted the hit structures according to the loop length. Two, five, or nine loop residues were frequently observed; thus, three circularized variants (C163, C166, and C170) were constructed, prepared, and evaluated. All circularized variants demonstrated a higher thermal stability than linear G-CSF (L175). In particular, C166 that retained five connecting residues demonstrated apparent T
Language	English
Publishing date	2017-10-20
Publishing country	United States
Document type	Journal Article
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/acschembio.7b00776
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Article ; Online: Characterization of Conformational Ensembles of Protonated N-glycans in the Gas-Phase.

Re, Suyong / Watabe, Shigehisa / Nishima, Wataru / Muneyuki, Eiro / Yamaguchi, Yoshiki / MacKerell, Alexander D / Sugita, Yuji

Scientific reports

2018 Volume 8, Issue 1, Page(s) 1644

Abstract: Ion mobility mass spectrometry (IM-MS) is a technique capable of investigating structural changes of biomolecules based on their collision cross section (CCS). Recent advances in IM-MS allow us to separate carbohydrate isomers with subtle conformational ... ...

Abstract	Ion mobility mass spectrometry (IM-MS) is a technique capable of investigating structural changes of biomolecules based on their collision cross section (CCS). Recent advances in IM-MS allow us to separate carbohydrate isomers with subtle conformational differences, but the relationship between CCS and atomic structure remains elusive. Here, we characterize conformational ensembles of gas-phase N-glycans under the electrospray ionization condition using molecular dynamics simulations with enhanced sampling. We show that the separation of CCSs between isomers reflects folding features of N-glycans, which are determined both by chemical compositions and protonation states. Providing a physicochemical basis of CCS for N-glycans helps not only to interpret IM-MS measurements but also to estimate CCSs of complex glycans.
MeSH term(s)	Gases ; Ion Mobility Spectrometry ; Molecular Conformation ; Molecular Dynamics Simulation ; Polysaccharides/analysis ; Polysaccharides/chemistry
Chemical Substances	Gases ; Polysaccharides
Language	English
Publishing date	2018-01-26
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-018-20012-0
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Article: Conformational flexibility of N-glycans in solution studied by REMD simulations.

Re, Suyong / Nishima, Wataru / Miyashita, Naoyuki / Sugita, Yuji

Biophysical reviews

2012 Volume 4, Issue 3, Page(s) 179–187

Abstract: Protein-glycan recognition regulates a wide range of biological and pathogenic processes. Conformational diversity of glycans in solution is apparently incompatible with specific binding to their receptor proteins. One possibility is that among the ... ...

Abstract	Protein-glycan recognition regulates a wide range of biological and pathogenic processes. Conformational diversity of glycans in solution is apparently incompatible with specific binding to their receptor proteins. One possibility is that among the different conformational states of a glycan, only one conformer is utilized for specific binding to a protein. However, the labile nature of glycans makes characterizing their conformational states a challenging issue. All-atom molecular dynamics (MD) simulations provide the atomic details of glycan structures in solution, but fairly extensive sampling is required for simulating the transitions between rotameric states. This difficulty limits application of conventional MD simulations to small fragments like di- and tri-saccharides. Replica-exchange molecular dynamics (REMD) simulation, with extensive sampling of structures in solution, provides a valuable way to identify a family of glycan conformers. This article reviews recent REMD simulations of glycans carried out by us or other research groups and provides new insights into the conformational equilibria of N-glycans and their alteration by chemical modification. We also emphasize the importance of statistical averaging over the multiple conformers of glycans for comparing simulation results with experimental observables. The results support the concept of "conformer selection" in protein-glycan recognition.
Language	English
Publishing date	2012-09-01
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	2486483-3
ISSN	1867-2469 ; 1867-2450
ISSN (online)	1867-2469
ISSN	1867-2450
DOI	10.1007/s12551-012-0090-y
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Article ; Online: Structural Transition and Antibody Binding of EBOV GP and ZIKV E Proteins from Pre-Fusion to Fusion-Initiation State.

Lappala, Anna / Nishima, Wataru / Miner, Jacob / Fenimore, Paul / Fischer, Will / Hraber, Peter / Zhang, Ming / McMahon, Benjamin / Tung, Chang-Shung

Biomolecules

2018 Volume 8, Issue 2

Abstract: Membrane fusion proteins are responsible for viral entry into host cells—a crucial first step in viral infection. These proteins undergo large conformational changes from pre-fusion to fusion-initiation structures, and, despite differences in viral ... ...

Abstract	Membrane fusion proteins are responsible for viral entry into host cells—a crucial first step in viral infection. These proteins undergo large conformational changes from pre-fusion to fusion-initiation structures, and, despite differences in viral genomes and disease etiology, many fusion proteins are arranged as trimers. Structural information for both pre-fusion and fusion-initiation states is critical for understanding virus neutralization by the host immune system. In the case of Ebola virus glycoprotein (EBOV GP) and Zika virus envelope protein (ZIKV E), pre-fusion state structures have been identified experimentally, but only partial structures of fusion-initiation states have been described. While the fusion-initiation structure is in an energetically unfavorable state that is difficult to solve experimentally, the existing structural information combined with computational approaches enabled the modeling of fusion-initiation state structures of both proteins. These structural models provide an improved understanding of four different neutralizing antibodies in the prevention of viral host entry.
MeSH term(s)	Antibodies, Viral/immunology ; Ebolavirus/chemistry ; Ebolavirus/physiology ; Molecular Dynamics Simulation ; Protein Binding ; Viral Envelope Proteins/chemistry ; Viral Envelope Proteins/immunology ; Viral Envelope Proteins/metabolism ; Virus Internalization ; Zika Virus/chemistry ; Zika Virus/physiology
Chemical Substances	Antibodies, Viral ; Viral Envelope Proteins ; envelope glycoprotein, Ebola virus
Language	English
Publishing date	2018-05-10
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom8020025
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