Directing Membrane Pore and Stalk Formation in MD Simulations with Embedded Mechanical Devices

Abstract

Stalk and pore formation are two well-known examples of the membrane topological changes required in a host of cellular processes. Their intermediate states, however, involve rearrangements of only a few lipid and solvent molecules, making them hard to observe experimentally. Molecular simulations have suitable temporal/spatial resolution to observe these transitions and have suggested stalk(pore) formation paths where a hydrophobic(philic) bridge nucleates across a hydrophilic(phobic) slab. However, most simulations require biasing schemes that are susceptible to hysteresis near the topological transitions.Here we present a simulation method implementing a biasing scheme to reversibly direct pore formation and closure using a membrane embedded ‘mechanical device’. This ‘pore device’ biasing potential can be adjusted to open, close or restrain a pore, permitting exhaustive and rigorous sampling of intermediate states such as asymmetrical indentations and water wires spanning the hydrophobic slab. Importantly, an unbiased (lipid+solvent only) free energy landscape for poration can be obtained by reweighting. Preliminary tests suggest that a similar ‘stalk device’ can also direct stalk formation in the same manner.