Session: 06-08-04: Computational Modeling in Biomedical Applications

Paper Number: 147212

147212 - Rate-Dependent Dissociation Mechanism of Vwf-Platelet Binding Under Pulling Force: Insights From Molecular Dynamics and Monte Carlo Simulations 

Arterial thrombosis, a leading cause of global mortality, presents a significant health challenge with limited treatment options. Central to understanding thrombosis is the interaction between von Willebrand factor (VWF) and platelets via glycoprotein Ibα (GPIbα) receptors. As mechanical force increases, GPIbα exhibits complex behavior, transitioning between catch and slip bonds with VWF-A1. Two key mechanisms have been identified: GPIbα leucine-rich repeat (LRR) domain unfolding and GPIb-VWFA1 sliding-rebinding. In hyperlipidemia, the high cholesterol level causes softening of platelets, which slow down the build up of mechanical force under blood shear flow，exhibiting rate-dependdent behavior. Here, we employ all-atom molecular dynamics (MD) simulations to explore how force loading rates influence GPIb-VWFA1 binding stability. Our findings reveal a rate-dependent dissociation process: higher loading rates decrease the frequency of sliding-rebinding while increasing GPIbα leucine-rich repeat (LRR) domain unfolding, consistent with experimental data. Additionally, Monte Carlo simulations with a pseudoatom representation were utilized to investigate the sliding-rebinding mechanism, showing quantitative agreement with experimental data. This study advances our understanding of arterial thrombosis and provides insights for targeted therapeutic interventions.

Presenting Author: Rongguang Xu Brigham and Women’s Hospital and Harvard Medical School

Presenting Author Biography: Dr. Rong-Guang Xu is currently a Postdoctoral Research Fellow at Brigham and Women’s Hospital/Harvard Medical School, jointly supported by the University of Texas Medical Branch. He received his BS degree in Applied Physics from Wuhan University and earned his PhD degree in mechanical engineering at the George Washington University. His research specialty lies in multiscale computational physics. materials science and (bio)mechanics, especially in nanotribology, nanoconfinement, nanoindentation, computational nanomedicine, membrane-fouling in water treatment, and 2D piezoelectric materials for energy harvesting.

Authors:

Rongguang Xu Brigham and Women’s Hospital and Harvard Medical School
Zi Chen Brigham and Women’s Hospital and Harvard Medical School
Yunfeng Chen University of Texas Medical Branch