University of Pennsylvania Department of Bioengineering Hybrid Models For Protein-Membrane Interactions At Mesoscale: Bridge to Intracellular Signaling Neeraj Agrawal, Jonathan Nukpezah, Joshua Weinstein & Ravi Radhakrishnan University of Pennsylvania Clathrin University of Pennsylvania Department of Bioengineering Objectives Short-term Quantitative dynamic models for membrane invagination: Development of a multiscale approach to describe protein-membrane interaction at the mesoscale ( m) Long-term Integrating with flow and signal transduction Targeted Therapeutics University of Pennsylvania Department of Bioengineering Endocytosis: The Internalization Machinery in Cells Detailed molecular and physical mechanism of the process still evading. Endocytosis is a highly orchestrated process involving a variety of proteins. Attenuation of endocytosis leads to impaired deactivation of EGFR linked to cancer Membrane deformation and dynamics linked to nanocarrier adhesion to cells University of Pennsylvania Department of Bioengineering Length scale Time scale nm ns mm s Fully-atomistic MD Coarse-grained MD Generalized elastic model Bilayer slippage Monolayer viscous dissipation Viscoelastic model University of Pennsylvania Department of Bioengineering Elastic Model For Membrane Monge TDGL Helfrich membrane energy accounts for membrane bending and membrane area extension. In Monge notation, for small deformations, the membrane energy is Force acting normal to the membrane surface (or in z-direction) drives membrane deformation Spontaneous curvatureBending modulus Frame tension Splay modulus Consider only those deformations for which membrane topology remains same. White noise University of Pennsylvania Department of Bioengineering Hydrodynamics Non inertial Navier Stoke equation Dynamic viscosity Greens function of above PDE results in Oseen tensor, (Generalized Mobility matrix). Oseen tensor in infinite medium Fluid velocity is same as membrane velocity at the membrane boundary no slip condition For Monge TDGL, viscous dissipation within bilayer is irrelevant. Hydrodynamic coupling University of Pennsylvania Department of Bioengineering Epsin Diffusion Each epsin molecule induces a (additive) curvature field in the membrane Membrane in turn exerts a force on epsin Epsin performs a random walk on membrane surface with a bias dictated by force acting on epsin Diffusion in a force field on a 2 dimensional manifold No general analytical solution exist Bound epsin position University of Pennsylvania Department of Bioengineering Epsin Diffusion Solution propagated in time using kinetic monte carlo The elementary reaction characterized by rate: For 2 D Metric Where is the lattice size, F is the force acting on epsin, i.e. epsin(a) epsin(a+a 0 ) University of Pennsylvania Department of Bioengineering Hybrid Multiscale Integration Regime 1: Deborah number De