Free Energy Surface and Molecular Mechanism of Slow Structural Transitions in Lipid Bilayers.

Lipid membrane remodeling, crucial for many cellular processes, is governed by the coupling of membrane structure and shape fluctuations. Given the importance of the ∼ nm length scale, details of the transition intermediates for conformational change are not fully captured by a continuum-mechanical description. Slow dynamics and the lack of knowledge of reaction coordinates (RCs) for biasing methods pose a challenge for all-atom (AA) simulations. Here, we map system dynamics on Langevin dynamics in a normal mode space determined from an elastic network model representation for the lipid-water Hamiltonian. AA molecular dynamics (MD) simulations are used to determine model parameters, and Langevin dynamics predictions for bilayer structural, mechanical, and dynamic properties are validated against MD simulations and experiments. Transferability to describe the dynamics of a larger lipid bilayer and a heterogeneous membrane-protein system is assessed. A set of generic RCs for pore formation in two tensionless bilayers is obtained by coupling Langevin dynamics to the underlying energy landscape for membrane deformations. Structure evolution is carried out by AA MD, wherein the generic RCs are used in a path metadynamics or an umbrella sampling simulation to determine the thermodynamics of pore formation and its molecular determinants, such as the role of distinct bilayer motions, lipid solvation, and lipid packing.