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CC BY-NC-ND 4.0 · TH Open 2022; 06(04): e421-e428
DOI: 10.1055/a-1937-9940
Original Article

Physical Characteristics of von Willebrand Factor Binding with Platelet Glycoprotein Ibɑ Mutants at Residue 233 Causing Various Biological Functions

Masamitsu Nakayama
1   Department of Medicine (Cardiology), Tokai University School of Medicine, Isehara, Japan
,
Shinichi Goto
1   Department of Medicine (Cardiology), Tokai University School of Medicine, Isehara, Japan
,
Shinya Goto 
1   Department of Medicine (Cardiology), Tokai University School of Medicine, Isehara, Japan
› Author Affiliations Funding The authors acknowledged funding from grant-in-aid for MEXT/JSPS KAKENHI 19H03661, AMED grant number A368TS, A447TR, Bristol-Myers Squibb for an independent research support project (33999603) and a grant from Nakatani Foundation for Advancement of Measuring Technologies in Biomedical Engineering and Vehicle Racing Commemorative Foundation (6236). The author S.G. acknowledged partial financial support from Sanofi, Pfizer, Bristol Myer Squibb, and Ono Pharma.
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Abstract

Glycoprotein (GP: HIS1-PRO265) Ibɑ is a receptor protein expressed on the surface of the platelet. Its N-terminus domain binds with the A1 domain (ASP1269-PRO1472) of its ligand protein von Willebrand factor (VWF) and plays a unique role in platelet adhesion under blood flow conditions. Single amino acid substitutions at residue 233 from glycine (G) to alanine (A), aspartic acid (D), or valine (V) are known to cause biochemically distinct functional alterations known as equal, loss, and gain of function, respectively. However, the underlying physical characteristics of VWF binding with GPIbɑ in wild-type and the three mutants exerting different biological functions are unclear. Here, we aimed to test the hypothesis: biological characteristics of macromolecules are influenced by small changes in physical parameters. The position coordinates and velocity vectors of all atoms and water molecules constructing the wild-type and the three mutants of GPIbɑ (G233A, G233D, and G233V) bound with VWF were calculated every 2 × 10−15 seconds using the CHARMM (Chemistry at Harvard Macromolecular Mechanics) force field for 9 × 10−10 seconds. Six salt bridges were detected for longer than 50% of the calculation period for the wild-type model generating noncovalent binding energy of −1096 ± 137.6 kcal/mol. In contrast, only four pairs of salt bridges were observed in G233D mutant with noncovalent binding energy of −865 ± 139 kcal/mol. For G233A and G233V, there were six and five pairs of salt bridges generating −929.8 ± 88.5 and −989.9 ± 94.0 kcal/mol of noncovalent binding energy, respectively. Our molecular dynamic simulation showing a lower probability of salt bridge formation with less noncovalent binding energy in VWF binding with the biologically loss of function G233D mutant of GPIbɑ as compared with wild-type, equal function, and gain of function mutant suggests that biological functions of macromolecules such as GPIbɑ are influenced by their small changes in physical characteristics.

Keywords

platelet - von Willebrand factor - salt bridge - molecular dynamic

Supplementary Material



Publication History

Received: 20 May 2022

Accepted: 05 August 2022

Accepted Manuscript online:
07 September 2022

Article published online:
07 December 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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