Background: Platelet membrane glycoprotein (GP) Ibα binding with von Willebrand factor (VWF) exclusively mediates initial platelet adhesion at site of endothelial damage under blood flow conditions. Single amino-acid mutations, such as G233 in GPIbα were shown to lead to clinical phenotype by changing the adhesion characteristics of platelets.

Aims: To clarify salt bridge formation between VWF and GPIbα in various mutant at G233 Platelet GPIbα.

Methods: All atoms and water molecules constructing the N-terminus GPIbα domain containing leucine rich repeat (residues HSE¹-PRO²⁶⁵), A1 domain of VWF (residues ASP⁵⁰⁶-PRO⁷⁰³) were targeted for Molecular Dynamics (MD) calculation. The mutations are prepared with G233A (equal function), G233V (gain of function), and G233D (loss of function), already calculated in previous study. Salt bridges formed within 4 Å between VWF and GPIbα were calculated using the NAMD energy plugin implemented in VMD 1.9.4. The parameter file was using Chemistry at Harvard Macromolecular Mechanics (CHARMM)-36 force field.

Results: Salt bridges formed within 4 Å between VWF and GPIbα with various mutations were changed (Fig.1).

The list of salt bridges between VWF and GPIbα interaction. Salt bridges within 4 Å were shown in the list.

Non-bond potential energies were shown -1056.2 kcal/mol in wild type, -978.7 kcal/mol in G233A, -908.4 kcal/mol in G233V, and -903.1 kcal/mol in G233. The wild type was shown most stable energetic structure and G233D was less stable compared with others. The pair of amino acids consist of salt bridges of wild type and G233D are shown in Fig.2. In wild type, the salt bridges concentrated in N-terminus side. In G233D, salt bridges were sparse compared with wild type.

The pair of amino acids consist of salt bridges of wild type and G233D. The circle showed the interactions of two or three amino-acid in salt bridge.

Conclusions: Mutation at G233 influence biological function of GPIbα by changed salt bridge formation between VWF.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/salt-bridge-formation-between-a1-domain-of-von-willebrand-factor-and-platelet-glycoprotein-gp-ib%ce%b1-by-molecular-dynamics-simulations/