Mapping the free-energy landscape of trans-membrane pores by atomistic molecular dynamics simulations

NORA A. E. MOYANO; JOAQUÍN KLUG; CARLES TRIGUERO; GARETH A. TRIBELLO; NIALL ENGLISH; JORGE J. KOHANOFF; VANESA GALASSI; DANIEL MILLÁN; MARIO G. DEL PÓPOLO

Mendoza

Simposio; II Simposio de Medicina Traslacional; 2019

Facultad de Ciencias Médicas de la Universidad Nacional de Cuyo

Introduction. When lipid membranes are submitted to mechanical or electrical stress, the formation of pores and water channels leads to concomitant changes in water permeability and ionic conductivity. Membrane defects, and membrane pores in particular, are involved in physiological processes at the cellular level and affect, among other things, the transport of drugs and metabolites through the lipid bilayer. The Aim of present work was to produce a free-energy map that allows to identify the formation energy and nucleation mechanism of transmembrane pores with different sizes and levels of hydration. Methods. We resort to 2D meta-dynamics simulations. We make use of two complementary collective variables, Xi and Phi. The first one controls the lipid density around a specified point on the membrane plane and thus allows to create a pore, and the last one controls the number of water molecules inside the pore.Results. We present preliminary results for an atomistic POPC bilayer. When Xi=0, the trajectories show configuration in which the formation of percolating water wires across the bilayer and hydrophobic pores is evident. For Phi=0, frames with vapor pores of different radius are observed. For values of Xi≠0 and Phi≠0, we observe a combination of the previous hydrophobic pores, vapor pores and hydrophilic pores.Conclusions. Our results suggest that at least two collective variables are required to map the free-energy landscape associated to the formation of hydrophobic, vapor, and hydrophilic transmembrane pores.