Brownian adhesive dynamic (BRAD) simulations for modeling viral attachment to cell

Multivalent binding of nanometer particles is a difficult modeling problem. Previous methods have assumed that multivalent binding events can be modeled as well-mixed monovalent reactions. This assumption is known as the equivalent site hypothesis (ESH). This thesis presents the development of Brownian Adhesive Dynamics (BRAD) a simulation method used to test ESH and expand multivalent nanometer particle binding models. The simulation couples the thermal motion of nanometer scale particles with adhesive dynamics models to characterize the effect of bonding on the particle.;Viruses are multivalent nanometer scale particles. Binding of HIV-like particles to CD4 expressing cells is the model system used to illustrate the utility of BRAD. Comparison of the transition rates between bound states predicted by ESH and the rates resulting from BRAD simulations show dramatic differences. Using kinetic constants from experimentally measured binding between individual gp120 and CD4 molecules, ESH suggests all virus adhesion proteins will be bound (KxRT = 106), while BRAD predicts not all virus adhesion proteins will be bound. At values of the equilibrium crosslinking constant used in typical ESH calculations of virus docking (Kx RT = 1) BRAD simulations predict no binding. The mean bond density from BRAD models is often much lower than that predicted by ESH for equivalent parameter values. BRAD suggests that the viruses are much less well bound than ESH predicts.;The flexibility of BRAD has allowed it to be extended to include the motion of proteins within the cellular membrane. Incorporation of membrane protein diffusion into the model shows that the reaction between ligand and receptor is faster than diffusive transport of receptor. Also, it demonstrates that a successful virus/cell collision is determined well before receptor transport into the contact area can play a role in binding. Lastly, membrane deformation modeling has been coupled with BRAD simulations. Results from these calculations suggest that viruses cannot engineer their own entry into cells, and must trick cells into taking an active role in virus uptake.