Free energy surface and molecular characterization of slow structural transitions in lipid bilayers

The need to incorporate specific molecular-scale features for largescale structural changes in biological membranes necessitate use of a multi-scale computational approach. Here, this comprises of Langevin dynamics in a normal mode space determined from an elastic network model (ENM) representation for lipid-water Hamiltonian. All atom (AA) MD simulations are used to determine model parameters, and Langevin dynamics predictions for an extensive set of bilayer properties, such as, undulation spectra, undulation relaxation rates, dynamic structure factor, and mechanical properties are validated against the data from MD simulations and experiments. The transferability of model parameters to describe dynamics of a larger lipid bilayer and a heterogeneous membrane-protein system is assessed. The developed model is coupled to the energy landscape for membrane deformations to obtain a set of generic reaction coordinates (RCs) for pore formation in two tensionless, single lipid-type bilayers, namely, 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC). Structure evolution is carried in an AA MD simulation wherein the generic RCs are used in a path metadynamics or an umbrella sampling simulation to investigate thermodynamics of pore formation and its molecular determinants. The transition state is characterized extensively to bring out the interplay between various bilayer motions (undulations, lateral density fluctuations, thinning, lipid tilt), lipid solvation, and lipid packing.