On The Transition Region Of Transmembrane Pores

Trans-membrane pores are transient structures that play an important role in translocation of small molecules and peptides across cell membranes. Cell-penetrating and anti-microbial peptides act via pore-mediated mechanisms. Characterizing the free energy landscape of pore-formation is thus required for understanding membrane permeation or for designing antimicrobial peptides. We calculated free energy profiles for trans-membrane pore formation from atomistic molecular dynamics simulations using the umbrella sampling method. Three reaction coordinates were used for the umbrella sampling simulations; a) The radial collective reaction coordinate by Wohlert et al [1], b) distance of a single lipid phosphate from the center of the membrane by Tieleman et al [2], and c) water density-based reaction coordinate [3]. Ideally, a reaction coordinate should efficiently sample the transition region of pore formation. However, none of the three reaction coordinates [1-3] is capable of sampling the transition region efficiently. We observe large differences in the number of water molecules inside the pore, between opening and closing simulations, even after long simulation times, indicative of strong hysteresis effects. Closer inspection of the simulations shows that the transition region of a pore formation is characterized by the formation and disruption of a continuous channel of water. Our work provides molecular insights into pore formation and closure, and paves the route to unravel the free energy landscape of trans-membrane pores.1. J. Chem. Phys., 2006, 124, 154905.2. Soft Matter, 2009, 5, 3295.3. J. Chem. Theory Comput., 2015, 11(1), 343.