Multiscale modeling of nanocarrier binding to endothelium
Targeted drug delivery using functionalized nanocarriers can improve the efficacy vascular drug therapies. We have developed a multiscale model which describes the binding between a nanocarrier and the endothelial cell surface in good agreement with experiments  . The model consists of two components: a mesoscale description of multivalent antigen-antibody interactions and coarse-grained molecular dynamics (CGMD) simulations of the antigen, intracellular adhesion molecule-1 (ICAM-1). At the mesoscale, we applied Metropolis Monte Carlo (MC) and the weighted histogram analysis method (WHAM) to compute the free energy landscape, or potential of mean force (PMF), of nanocarrier binding. Computing the absolute binding free energy while accounting for translational and rotational entropy losses gives the corresponding binding affinities. At the molecular level, fluctuation analysis of CGMD simulations of ICAM-1 was used to estimate its flexural rigidity, which was used as a parameter in the mesoscale model. All other free parameters were determined from independent cell biology experiments with no fitting. The predicted PMF aligns closely with a wide range of measurements, including in vitro cell culture, in vivo endothelial targeting and atomic force microscopy. This multiscale protocol provides a quantitative approach for functionalized nanocarrier design and optimization in targeted vascular drug delivery. Additionally, the combination of near-molecular resolution of CGMD with mesoscale models probed by MC methods provides a template for bottom-up multiscale modeling approaches, which we can apply to other systems, namely membrane curvature induction by epsin and clathrin in endocytosis.
Liu, J.; Weller, G.; Zern, B.; Ayyaswamy, P. S.; Eckmann, D. M.;
Muzykantov, V. R.; Radhakrishnan, R., Computational model for
nanocarrier binding to endothelium validated using in vivo, in vitro
and atomic force microscopy experiments. Proc.
Natl. Acad. Sci. USA
107, (38), 16530-16535.
 Liu, J.; Bradley, R.; Ayyaswamy, P. S.; Eckmann, D. M. & Radhakrishnan, R. Computer-Aided Design of Functionalized Nanocarriers in Targeted Drug Delivery. Submitted for publication, Current Nanoscience.
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