Exploring Receptor-mediated Endocytosis of Bioparticles through Multiscale Modeling

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PI: Liu, JinPropsal #: 1604211Internalization of bioparticles bound to a cell's surface (endocytosis), such as viruses and drug carriers, through receptor-mediated endocytosis (RME) plays essential roles in fundamental understanding of viral infections and targeted drug deliveries. RME of bioparticles is a highly complex and multiscale process that is difficult to investigate through scale-specific techniques. The goal of this three-year project is to establish an interdisciplinary research program in investigating RME of bioparticles through multiscale modeling and simulations. Model simulations will be used 1) to make energy calculations, 2) to investigate the effects of particle size/shape, ligand density/type and molecular interactions on the overall process and 3) to explore applications in brain drug delivery across the blood-brain barrier and herpes simplex virus prevention. Findings will have broad scientific and technological impact in the fields of virus infection and intracellular/transcelluar targeted drug delivery using nanocarriers, nutrition uptake, contrast-based imaging and cancer progression/metastasis. Results may lead to a rational design and engineering for effective drug delivery and novel strategies for viral intervention and inhibition. Educational impact is advanced through the unique interdisciplinary training students will receive and opportunities provided for K-12 via summer camps, lab experiences and collaboration with a local science center. This award is cofunded by the Mathematical Biology program in the Division of Mathematical Sciences through the BioMaPs program. Internalization of bioparticles, such as viruses and drug carriers, through receptor-mediated endocytosis (RME) plays essential roles in fundamental understanding of viral infections and intracellular/transcellular targeted drug deliveries. RME of bioparticles is a highly complex and multiscale process, which is difficult to investigate through scale-specific techniques (both experimentally and numerically). The goal of this three-year project is to establish an interdisciplinary research program in investigating RME of bioparticles through multiscale modeling and simulations. The research objectives are: 1) to develop a 3D mesoscale stochastic model for binding and internalization of bioparticles, the mesoscopic model is a combination of a stochastic binding model with a mesoscopic membrane model based on the discretization of Helfrich Hamiltonian on a curvilinear space using Monte Carlo method; 2) to implement coarse-grained molecular dynamics simulations to investigate the molecular events in RME and then develop the multiscale model by coupling the atomistic simulations with the mesoscopic model through sequential and concurrent methods; and 3) to perform free energy calculations using our multiscale model and investigate the effects of particle size/shape, ligand density/type, as well as the molecular interactions on the overall process of RME, and explore the applications in brain drug delivery across blood-brain barrier and herpes simplex virus prevention. The multiscale model will provide a unified and coherent description of the process by accounting for effects from both mesoscopic and atomistic effects. The simulations will bring critical, new insight and a deeper understanding of the mechanism of RME. Innovations of the proposal include: 1) the integration of atomistic simulations with mesoscopic model, 2) the combination of the membrane model with the stochastic binding model that enables exploration of endocytosis with extreme deformations and 3) the coarse-grained force field in atomistic simulations that enables the capture of structural (conformational) information for protein-protein interactions during RME. The multiscale models, together with the free energy calculations, create natural links between different functional biological scales and enables direct and indirect correlations between modeling results and experimental data. Findings will have broad scientific and technological impact in the fields of virus infection and intracellular/transcelluar targeted drug delivery using nanocarriers, nutrition uptake, contrast-based imaging and cancer progression/metastasis and results may lead to a rational design and engineering for effective drug delivery, and novel strategies for viral intervention and inhibition. The students supported by the grant will have opportunities to receive a unique interdisciplinary training across the mechanical engineering and bioengineering, learn the cutting-edge multiscale numerical modeling techniques, which enable them to become leaders in the bio/nanotechnology field. The involvement of under-represented minority students will be coordinated with existing LSAMP and SWE programs. The findings from the proposed research will be broadly disseminated to K-12 students through outreach activities in WSU and collaboration with local science center, including participation in summer camps and creation of a 3D visualization platform for interactive exploration and modeling of biomolecular events with atomic-scale resolution.