(702h) Multiscale Modeling of Nanocarrier Binding to Endothelium

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 [1] [2].
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.

[1]
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
2010,
107, (38), 16530-16535.
[2] 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.