Rare Event Prediction of Von Willebrand Factor Multimer Unfolding in Extensional Flow

Abstract

Extensional flow-induced transitions from a compact to an unfolded conformation are explored for the wild type (WT) human glycoprotein von Willebrand factor (vWF). Multimer unfolding is a crucial step in the process of blood clotting and protein size maintenance. Previous studies have shown that a thermally nucleated polymeric protrusion initiates flow-induced conformational transition. Below a certain strain rate, such a transition is a rare event that cannot be studied using standard stochastic dynamic simulation. In the present study, we have employed Weighted Ensemble Brownian dynamic (WEBD) simulations to predict rare conformation transition events in extensional flow. Results are presented for the transition rate of WT vWF multimer unfolding, with concomitant analysis of the likelihood of pathological unfolding as a function of strain rate. The multimer size explored here is 80-monomers, which is near the upper end of the hemostatically active size range for WT vWF. To detect potentially pathological flow, the mean first passage time (MFPT) for multimer unfolding from the compact to the elongated conformation was computed and compared to the half-life of vWF proteins in the human body, which is estimated to be 8-12 hours. The MFPT predicted from WEBD simulations for extension rate 2000s−1 is 1.25 hours; for strain rate 1500s−1 the predicted MFPT increases to 315.8 hours, which is significantly larger than the WT vWF half-life. Results here indicate that even periodic exposure of vWF proteins to extensional flow greater than or equal to 2000s−1 may result in pathological unfolding.