PB0381 - Impact of Coagulation Factor XI (FXI) on the Binding of Platelet Glycoprotein Ibα to the von Willebrand Factor A1 Domain

Sunday, July 10, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Presenting Author(s)

Masamitsu Nakayama

Researcher
Tokai University School of Medicine
Isehara, Kanagawa, Japan

Co-Author(s)

SG

Shinichi Goto

Associate Professor
Tokai University School of Medicine
Isehara, Kanagawa, Japan
ST

Satoko Takemoto

Research associate
Image Processing Research Team, Center for Advanced Photonics, RIKEN
Wako, Saitama, Japan
HO

Hideki Oka

Visiting professor
Department of Medicine (Cardiology), Tokai University School of Medicine
Isehara, Kanagawa, Japan
HY

Hideo Yokota

Team Leader
Image Processing Research Team, Center for Advanced Photonics, RIKEN
Wako, Saitama, Japan
ST

Shu Takagi

Professor
Graduate School of Engineering, The University of Tokyo
Bunkyō, Tokyo, Japan
SG

Shinya Goto

Professor
Tokai University Shcool of Medicine
Isehara, Kanagawa, Japan

Background: Platelet glycoprotein (GP)Ibα have specific binding sites for multiple proteins such as von Willebrand factor (VWF) and coagulation factor XI (FXI). The structural basis for different biological functions mediated by FXI and VWF binding with GPIbα is still to be elucidated.

Aims: To clarify the potential impacts of FXI binding to GPIbα-VWF complex using MD simulations.

Methods: The binding site(s) of FXI on GPIbα is not fully known. Since K252 and K253 in FXI are positively charged amino acids, all negatively charged amino acids (GLU and ASP) in targeted N-terminus GPIbα were assumed to be potential binding sites for FXI in this study (Fig.1). The position and velocity vector of each atom and water molecule were calculated in each 2×10-15 second with NAnoMolecular Dynamics (NAMD) software using Chemistry at Harvard Macromolecular Mechanics (CHARMM)-36 force field. All models were calculated 450 ns.

Results: The molecular dynamic simulation revealed approximately 4.2 to 27.3 times greater positional fluctuations in atoms constructing GPIbα bound with FXI as compared to its binding with VWF. Non-covalent binding energy generated by GPIbα binding with FXI is approximately 5% to 45% as compared to those generated by its binding with VWF. The structure of GPIbα binding with VWF is stable with minimal influence by its additional binding with FXI (Fig.2), which was confirmed by biological experiments in exogenously added FXI condition (final concentration of 80 µg/mL) showing no significant difference in platelet adhesion on VWF under wall shear rate of 1,500 s-1.

Conclusion(s): FXI binding with GPIbα minimally influenced the structure and biological function of GPIbα binding with VWF.