A Stochastic Molecular Dynamics Method for Multiscale Modeling of Blood Platlet Pheonmena

Brown University, Providence RI

Investigators

Abstract

It is now well established that platelet aggregation is not only important for primary hemostasis but, when exaggerated, can also lead to the formation of occlusive thrombi, which form at sites of atherosclerotic plaque rupture, resulting in a heart attack, stroke or sudden death. Platelets are micron-size cells - smaller than red blood cells - and when activated they become adhesive for other activated platelets and they adhere to the vessel wall. Their strong interaction with nano-size proteins at the sub-endothelium matrix activates and reshapes them from passively traveling discoids to active spiny spheres. The length and time scales characterizing such interactions as well as platelet-blood flow interactions span several orders of magnitude. We propose a multiscale modeling methodology with focus on flow-modulated phenomena such as platelet adhesion and aggregation at the micron-scale, and including nanoscale effects representing the main protein interactions. We will develop an integrated approach by coupling multiscale representations of blood flow, ranging from a quasi 1D transient flow in compliant vessels at the largest scale, to unsteady 3D flows in curved and flexing vessels at the mm range, to multi micron-scale thrombus formation at a fissure in the lumen of such a vessel with an atherosclerotic plaque, to changes over short times (seconds and minutes) in the behavior of platelet structure, receptors and bonds in a developing thrombus-wall interaction. To this end, we will develop a new mesoscopic numerical method that bridges the gap between atomistic phenomena and large-scale phenomena to seamlessly connect length scales from 10 nm to a few mm. The new simulation approach will be validated systematically against experiments of varying biological and computational complexity. We also propose to establish a virtual center for multiscale modeling in order to provide modelers and experimentalists with quantitative information about molecular and cellullar processes that can be incorporated into simplified models. To this end, we plan to organize a workshop on multiscale modeling of biological processes during the second year of the proposed project. In our outreach program, we plan to engage pre-college women from the Providence area in computer and computational sciences. This will involve lectures by our medical collaborators as well as interactive learning at Brown's virtual immersive visualization facility. The potential impact of this work is great as it provides a new simulation capability for studying biomolecular interactions in blood vessels, organs and the entire arterial tree in a few hours instead of days or even weeks on a supercomputer. This, in turn, will allow fundamental studies at the molecular and cellular level and interaction with macroscales not currently possible with existing methodologies.