Prediction of binding characteristics between von Willebrand factor and platelet glycoprotein Ibα with various mutations by molecular dynamic simulation

Shinichi Goto, Hideki Oka, Kengo Ayabe, Hiroto Yabushita, Masamitsu Nakayama, Terumitsu Hasebe, Hideo Yokota, Shu Takagi, Motoaki Sano, Aiko Tomita, Shinya Goto

Research output: Contribution to journalArticle

Abstract

Introduction: Binding of platelet glycoprotein (GP)Ibα with von-Willebrand factor (VWF) exclusively mediates the initial platelet adhesion to injured vessel wall. To understand the mechanism of biomedical functions, we calculated the dynamic fluctuating three-dimensional (3D) structures and dissociation energy for GPIbα with various single amino-acid substitution at G233, which location is known to cause significant changes in platelet adhesive characteristics. Material and methods: Molecular dynamics (MD) simulation was utilized to calculate 3D structures and Potential of Mean Force (PMF) for wild-type VWF bound with wild-type, G233A (equal function), G233V (gain of function), and G233D (loss of function) GPIbα. Simulation was done on water-soluble condition with time-step of 2 × 10 15 s using NAnoscale Molecular Dynamics (NAMD) with Chemistry at HARvard Molecular Mechanics (CHARMM) force field. Initial structure for each mutant was obtained by inducing single amino-acid substitution to the stable water-soluble binding structure of wild-type. Results: The most stable structures of wild-type VWF bound to GPIbα in wild-type or any mutant did not differ. However, bond dissociation energy defined as difference of PMF between most stable structure and the structure at 65 Å mass center distances in G233D was 4.32 kcal/mol (19.5%) lower than that of wild-type. Approximately, 2.07 kcal/mol energy was required to dissociate VWF from GPIbα with G233V at mass center distance from 48 to 52 Å, which may explain the apparent “gain of function” in G233V. Conclusion: The mechanism of substantially different biochemical characteristics of GPIbα with mutations in G233 location was predicted from physical movement of atoms constructing these proteins.

Original languageEnglish
Pages (from-to)129-135
Number of pages7
JournalThrombosis Research
Volume184
DOIs
Publication statusPublished - 2019 Dec

Fingerprint

Platelet Glycoprotein GPIb-IX Complex
Platelet Membrane Glycoproteins
von Willebrand Factor
Molecular Dynamics Simulation
Mutation
Amino Acid Substitution
Blood Platelets
Water
Mechanics
Adhesives
Proteins

Keywords

  • Molecular dynamic
  • Platelet
  • Platelet glycoprotein
  • Thrombosis
  • von Willebrand factor

ASJC Scopus subject areas

  • Hematology

Cite this

Prediction of binding characteristics between von Willebrand factor and platelet glycoprotein Ibα with various mutations by molecular dynamic simulation. / Goto, Shinichi; Oka, Hideki; Ayabe, Kengo; Yabushita, Hiroto; Nakayama, Masamitsu; Hasebe, Terumitsu; Yokota, Hideo; Takagi, Shu; Sano, Motoaki; Tomita, Aiko; Goto, Shinya.

In: Thrombosis Research, Vol. 184, 12.2019, p. 129-135.

Research output: Contribution to journalArticle

Goto, Shinichi ; Oka, Hideki ; Ayabe, Kengo ; Yabushita, Hiroto ; Nakayama, Masamitsu ; Hasebe, Terumitsu ; Yokota, Hideo ; Takagi, Shu ; Sano, Motoaki ; Tomita, Aiko ; Goto, Shinya. / Prediction of binding characteristics between von Willebrand factor and platelet glycoprotein Ibα with various mutations by molecular dynamic simulation. In: Thrombosis Research. 2019 ; Vol. 184. pp. 129-135.
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abstract = "Introduction: Binding of platelet glycoprotein (GP)Ibα with von-Willebrand factor (VWF) exclusively mediates the initial platelet adhesion to injured vessel wall. To understand the mechanism of biomedical functions, we calculated the dynamic fluctuating three-dimensional (3D) structures and dissociation energy for GPIbα with various single amino-acid substitution at G233, which location is known to cause significant changes in platelet adhesive characteristics. Material and methods: Molecular dynamics (MD) simulation was utilized to calculate 3D structures and Potential of Mean Force (PMF) for wild-type VWF bound with wild-type, G233A (equal function), G233V (gain of function), and G233D (loss of function) GPIbα. Simulation was done on water-soluble condition with time-step of 2 × 10− 15 s using NAnoscale Molecular Dynamics (NAMD) with Chemistry at HARvard Molecular Mechanics (CHARMM) force field. Initial structure for each mutant was obtained by inducing single amino-acid substitution to the stable water-soluble binding structure of wild-type. Results: The most stable structures of wild-type VWF bound to GPIbα in wild-type or any mutant did not differ. However, bond dissociation energy defined as difference of PMF between most stable structure and the structure at 65 {\AA} mass center distances in G233D was 4.32 kcal/mol (19.5{\%}) lower than that of wild-type. Approximately, 2.07 kcal/mol energy was required to dissociate VWF from GPIbα with G233V at mass center distance from 48 to 52 {\AA}, which may explain the apparent “gain of function” in G233V. Conclusion: The mechanism of substantially different biochemical characteristics of GPIbα with mutations in G233 location was predicted from physical movement of atoms constructing these proteins.",
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T1 - Prediction of binding characteristics between von Willebrand factor and platelet glycoprotein Ibα with various mutations by molecular dynamic simulation

AU - Goto, Shinichi

AU - Oka, Hideki

AU - Ayabe, Kengo

AU - Yabushita, Hiroto

AU - Nakayama, Masamitsu

AU - Hasebe, Terumitsu

AU - Yokota, Hideo

AU - Takagi, Shu

AU - Sano, Motoaki

AU - Tomita, Aiko

AU - Goto, Shinya

PY - 2019/12

Y1 - 2019/12

N2 - Introduction: Binding of platelet glycoprotein (GP)Ibα with von-Willebrand factor (VWF) exclusively mediates the initial platelet adhesion to injured vessel wall. To understand the mechanism of biomedical functions, we calculated the dynamic fluctuating three-dimensional (3D) structures and dissociation energy for GPIbα with various single amino-acid substitution at G233, which location is known to cause significant changes in platelet adhesive characteristics. Material and methods: Molecular dynamics (MD) simulation was utilized to calculate 3D structures and Potential of Mean Force (PMF) for wild-type VWF bound with wild-type, G233A (equal function), G233V (gain of function), and G233D (loss of function) GPIbα. Simulation was done on water-soluble condition with time-step of 2 × 10− 15 s using NAnoscale Molecular Dynamics (NAMD) with Chemistry at HARvard Molecular Mechanics (CHARMM) force field. Initial structure for each mutant was obtained by inducing single amino-acid substitution to the stable water-soluble binding structure of wild-type. Results: The most stable structures of wild-type VWF bound to GPIbα in wild-type or any mutant did not differ. However, bond dissociation energy defined as difference of PMF between most stable structure and the structure at 65 Å mass center distances in G233D was 4.32 kcal/mol (19.5%) lower than that of wild-type. Approximately, 2.07 kcal/mol energy was required to dissociate VWF from GPIbα with G233V at mass center distance from 48 to 52 Å, which may explain the apparent “gain of function” in G233V. Conclusion: The mechanism of substantially different biochemical characteristics of GPIbα with mutations in G233 location was predicted from physical movement of atoms constructing these proteins.

AB - Introduction: Binding of platelet glycoprotein (GP)Ibα with von-Willebrand factor (VWF) exclusively mediates the initial platelet adhesion to injured vessel wall. To understand the mechanism of biomedical functions, we calculated the dynamic fluctuating three-dimensional (3D) structures and dissociation energy for GPIbα with various single amino-acid substitution at G233, which location is known to cause significant changes in platelet adhesive characteristics. Material and methods: Molecular dynamics (MD) simulation was utilized to calculate 3D structures and Potential of Mean Force (PMF) for wild-type VWF bound with wild-type, G233A (equal function), G233V (gain of function), and G233D (loss of function) GPIbα. Simulation was done on water-soluble condition with time-step of 2 × 10− 15 s using NAnoscale Molecular Dynamics (NAMD) with Chemistry at HARvard Molecular Mechanics (CHARMM) force field. Initial structure for each mutant was obtained by inducing single amino-acid substitution to the stable water-soluble binding structure of wild-type. Results: The most stable structures of wild-type VWF bound to GPIbα in wild-type or any mutant did not differ. However, bond dissociation energy defined as difference of PMF between most stable structure and the structure at 65 Å mass center distances in G233D was 4.32 kcal/mol (19.5%) lower than that of wild-type. Approximately, 2.07 kcal/mol energy was required to dissociate VWF from GPIbα with G233V at mass center distance from 48 to 52 Å, which may explain the apparent “gain of function” in G233V. Conclusion: The mechanism of substantially different biochemical characteristics of GPIbα with mutations in G233 location was predicted from physical movement of atoms constructing these proteins.

KW - Molecular dynamic

KW - Platelet

KW - Platelet glycoprotein

KW - Thrombosis

KW - von Willebrand factor

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