Nanoscale particle binding in silico: HIV docking and multivalent recruitment under flow
Enveloped viral infection is mediated by the binding of viral proteins with host cell receptors. Small particles are capable of binding with multiple receptors making the calculation of the multivalent saturation state difficult. This dissertation presents a computer simulation model to study the binding of biologically relevant proteins on the surface of nanoscale particles. The prototype of these studies is HIV binding CD4+ host cells. ^ We investigate the role of cellular receptor diffusion on the degree of binding achieved by the virus on both short timescales (where binding has reached steady state, but before substantial receptor accumulation in the viral-cell contact zone has occurred) and long timescales (where the system has reached steady state). On short timescales, viruses with 10-23 env trimers most efficiently form fully engaged trimers. On long timescales, all gp120 in the contact area become bound to CD4. Extending these calculations to include the packing volume of cellular receptors in the contact area reveals that a maximum of 6 env trimers can be fully engaged to both CD4 and CCR5. The time to reach a saturated state is exponentially related to the total number of proteins in the contact area. Finally, we study the effects of cellular coreceptor density on the time to reach a fully saturated state. We predict that combined therapy of two entry inhibiting agents, T-20 and maraviroc, will have synergistic efficacy against viral infection. ^ We use simulations to study the binding of engineered particles to coated surfaces with the goal of predicting multivalent binding in vivo. For systems under flow, the multivalent potential of particle binding does not improve the particle recruitment to a surface, however a higher bond number increases the bound lifetime of the particle. Therefore, the off rate, kr, of the protein interactions is important in tuning the multivalent binding of nanoscale particles. We reconstructed the binding phase of binding experiments monitored with surface plasmon resonance using simulations of particle. Our predicted values of peak binding closely correspond with the measured binding in BIAcore experiments. ^
Engineering, Biomedical|Biology, Virology|Biophysics, General
Andrew Daniel Trister,
"Nanoscale particle binding in silico: HIV docking and multivalent recruitment under flow"
(January 1, 2007).
Dissertations available from ProQuest.