Wataru Nishima | University of New Mexico (original) (raw)
Papers by Wataru Nishima
Biophysical Journal, Feb 1, 2023
Biophysical Reviews, Sep 1, 2012
Protein-glycan recognition regulates a wide range of biological and pathogenic processes. Conform... more 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. Keywords N-glycan. Conformational flexibility. Protein-glycan interactions. N-glycan modifications. Conformer selection. Molecular dynamics simulations. Replica-exchange molecular dynamics simulations Conformational flexibility of glycans Glycan is an essential molecular component in biological systems. In mammals, there are about ten types of monosaccharides that are used to form glycans. These monosaccharides are linked together by various glycosidic bonds. The addition of branch structures further matures glycans, making them distinct from proteins and DNA (Werz et al. 2007). The coexistence of rigid (saccharides) and flexible (glycosidic linkage) units in the glycan molecule gives rise to distinct multiple conformations in solution. This conformational diversity is also shown in glycans that are covalently attached to proteins and lipids. The glycan-bound proteins and lipids participate in many key biological processes including cell adhesion, molecular trafficking and clearance, receptor activation, signal transduction, and endocytosis (Ohtsubo and Marth 2006). Most of the biological functions of glycans rely on their binding to receptor proteins like lectin. Single-sitebinding affinity in lectin is generally low (with K d values in the micromolar range), but highly specific. The relation between the flexibility of glycans and their specific recognition remains elusive. Protein-glycan interactions have been considered to be based on "conformer selection" (Gabius et al. 2011; Gabius 2008).
Scientific Reports, Jan 26, 2018
Ion mobility mass spectrometry (IM-MS) is a technique capable of investigating structural changes... more 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 gasphase 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.
Nucleic Acids Research
Translocation of messenger RNA (mRNA) and transfer RNA (tRNA) substrates through the ribosome dur... more 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, withi...
doi:10.1093/bioinformatics/btp032 Structural bioinformatics and data mining DTA: dihedral transit... more doi:10.1093/bioinformatics/btp032 Structural bioinformatics and data mining DTA: dihedral transition analysis for characterization of the effects of large main-chain dihedral changes in proteins
Biophysical Journal, 2017
Covalent modifications and replication errors lead to DNA damage and mutation. Such errors occur ... more Covalent modifications and replication errors lead to DNA damage and mutation. Such errors occur frequently throughout the genome, disrupting the stability of the double helix. The 8-oxoguanine (8-oxoG) lesion, one of the most 68a Sunday,
Journal of Molecular Graphics and Modelling, 2010
Bioinformatics, 2009
Motivation: The biological function of proteins is associated with a variety of motions, ranging ... more Motivation: The biological function of proteins is associated with a variety of motions, ranging from global domain motion to local motion of side chain. We propose a method, dihedral transition analysis (DTA), to identify significant dihedral angle changes between two distinct protein conformations and for characterization of the effect of these transitions on both local and global conformation. Results: Applying DTA to a comprehensive and non-redundant dataset of 459 high-resolution pairs of protein structures, we found that a dihedral transition occurs in 82% of proteins. Multiple dihedral transitions are shown to occur cooperatively along the sequence, which allows us to separate a polypeptide chain into fragments with and without transitions, namely transition fragments (TFs) and stable fragments (SFs), respectively. By characterizing the magnitude of TF conformational change and the effect of the transition on the neighboring fragments, flap and hinge motions are identified as typical motions. DTA is also useful to detect protein motions, subtle in RMSD but significant in terms of dihedral angle changes, such as the peptide-plane flip, the side-chain flip and path-preserving motions. We conclude that DTA is a useful tool to extract potential functional motions, some of which might have been missed using conventional methods for protein motion analysis.
The SARS-CoV-2 virus has now become one of the greatest causes of infectious death and morbidity ... more 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 compr...
Viruses, 2021
The SARS-CoV-2 virus has now become one of the greatest causes of infectious death and morbidity ... more 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 comp...
Biomolecules, Jan 10, 2018
Membrane fusion proteins are responsible for viral entry into host cells—a crucial first st... more 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 st...
Journal of Computational Chemistry
Seibutsu Butsuri
Glycans-protein interaction is essential for a variety of biological functions and diseases. Howe... more Glycans-protein interaction is essential for a variety of biological functions and diseases. However, the inherent flexibility of the glycan molecules makes conventional X-ray or NMR structural analysis quite difficult. Here, we employ molecular dynamics (MD) simulations to reveal the glycanprotein complex structures in atomic details. To this end, we revised the current CHARMM force field for carbohydrates by refitting the parameters so as to increase the accuracy in the potential for the α1-6 glycosidic bond. Replica-exchange MD simulations, with extensive sampling of N-glycan structures in solution, show that our revised force filed parameters better reproduce the experimental NMR data and more accurately represent glycan rotameric conformations.
Seibutsu Butsuri
entered the FA zone via lateral difThsion in-on the PM, continuing diffusion even within the FA z... more entered the FA zone via lateral difThsion in-on the PM, continuing diffusion even within the FA zone {difYUsion coefiicient is V3 ofthat outside the FA), 11% Of Racl molecuTes that entered the FA zone exhibited temporary er long-term irnmobilization in the FA zone, suggesting thc binding to the FA island proteins, 19% Of Racl arrived at the FA zone directly frorn the cytoplasm and immobilized, suggesting that Racl is recruited to the FA protein islands both direct]y from the cytoplasrn and via the general PM area,
Biophysical Journal, Feb 1, 2023
Biophysical Reviews, Sep 1, 2012
Protein-glycan recognition regulates a wide range of biological and pathogenic processes. Conform... more 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. Keywords N-glycan. Conformational flexibility. Protein-glycan interactions. N-glycan modifications. Conformer selection. Molecular dynamics simulations. Replica-exchange molecular dynamics simulations Conformational flexibility of glycans Glycan is an essential molecular component in biological systems. In mammals, there are about ten types of monosaccharides that are used to form glycans. These monosaccharides are linked together by various glycosidic bonds. The addition of branch structures further matures glycans, making them distinct from proteins and DNA (Werz et al. 2007). The coexistence of rigid (saccharides) and flexible (glycosidic linkage) units in the glycan molecule gives rise to distinct multiple conformations in solution. This conformational diversity is also shown in glycans that are covalently attached to proteins and lipids. The glycan-bound proteins and lipids participate in many key biological processes including cell adhesion, molecular trafficking and clearance, receptor activation, signal transduction, and endocytosis (Ohtsubo and Marth 2006). Most of the biological functions of glycans rely on their binding to receptor proteins like lectin. Single-sitebinding affinity in lectin is generally low (with K d values in the micromolar range), but highly specific. The relation between the flexibility of glycans and their specific recognition remains elusive. Protein-glycan interactions have been considered to be based on "conformer selection" (Gabius et al. 2011; Gabius 2008).
Scientific Reports, Jan 26, 2018
Ion mobility mass spectrometry (IM-MS) is a technique capable of investigating structural changes... more 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 gasphase 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.
Nucleic Acids Research
Translocation of messenger RNA (mRNA) and transfer RNA (tRNA) substrates through the ribosome dur... more 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, withi...
doi:10.1093/bioinformatics/btp032 Structural bioinformatics and data mining DTA: dihedral transit... more doi:10.1093/bioinformatics/btp032 Structural bioinformatics and data mining DTA: dihedral transition analysis for characterization of the effects of large main-chain dihedral changes in proteins
Biophysical Journal, 2017
Covalent modifications and replication errors lead to DNA damage and mutation. Such errors occur ... more Covalent modifications and replication errors lead to DNA damage and mutation. Such errors occur frequently throughout the genome, disrupting the stability of the double helix. The 8-oxoguanine (8-oxoG) lesion, one of the most 68a Sunday,
Journal of Molecular Graphics and Modelling, 2010
Bioinformatics, 2009
Motivation: The biological function of proteins is associated with a variety of motions, ranging ... more Motivation: The biological function of proteins is associated with a variety of motions, ranging from global domain motion to local motion of side chain. We propose a method, dihedral transition analysis (DTA), to identify significant dihedral angle changes between two distinct protein conformations and for characterization of the effect of these transitions on both local and global conformation. Results: Applying DTA to a comprehensive and non-redundant dataset of 459 high-resolution pairs of protein structures, we found that a dihedral transition occurs in 82% of proteins. Multiple dihedral transitions are shown to occur cooperatively along the sequence, which allows us to separate a polypeptide chain into fragments with and without transitions, namely transition fragments (TFs) and stable fragments (SFs), respectively. By characterizing the magnitude of TF conformational change and the effect of the transition on the neighboring fragments, flap and hinge motions are identified as typical motions. DTA is also useful to detect protein motions, subtle in RMSD but significant in terms of dihedral angle changes, such as the peptide-plane flip, the side-chain flip and path-preserving motions. We conclude that DTA is a useful tool to extract potential functional motions, some of which might have been missed using conventional methods for protein motion analysis.
The SARS-CoV-2 virus has now become one of the greatest causes of infectious death and morbidity ... more 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 compr...
Viruses, 2021
The SARS-CoV-2 virus has now become one of the greatest causes of infectious death and morbidity ... more 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 comp...
Biomolecules, Jan 10, 2018
Membrane fusion proteins are responsible for viral entry into host cells—a crucial first st... more 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 st...
Journal of Computational Chemistry
Seibutsu Butsuri
Glycans-protein interaction is essential for a variety of biological functions and diseases. Howe... more Glycans-protein interaction is essential for a variety of biological functions and diseases. However, the inherent flexibility of the glycan molecules makes conventional X-ray or NMR structural analysis quite difficult. Here, we employ molecular dynamics (MD) simulations to reveal the glycanprotein complex structures in atomic details. To this end, we revised the current CHARMM force field for carbohydrates by refitting the parameters so as to increase the accuracy in the potential for the α1-6 glycosidic bond. Replica-exchange MD simulations, with extensive sampling of N-glycan structures in solution, show that our revised force filed parameters better reproduce the experimental NMR data and more accurately represent glycan rotameric conformations.
Seibutsu Butsuri
entered the FA zone via lateral difThsion in-on the PM, continuing diffusion even within the FA z... more entered the FA zone via lateral difThsion in-on the PM, continuing diffusion even within the FA zone {difYUsion coefiicient is V3 ofthat outside the FA), 11% Of Racl molecuTes that entered the FA zone exhibited temporary er long-term irnmobilization in the FA zone, suggesting thc binding to the FA island proteins, 19% Of Racl arrived at the FA zone directly frorn the cytoplasm and immobilized, suggesting that Racl is recruited to the FA protein islands both direct]y from the cytoplasrn and via the general PM area,