Phase Transition and Formation of Transmembrane Pore in Stretched Phospholipid Bilayer Including Cholesterol: Molecular Dynamics Simulation

Abstract

We perform molecular dynamics (MD) simulations of stretched phospholipid/cholesterol bilayers to understand effects of cholesterol on the dynamics of pore formation in the bilayer under mechanical stresses. The stretched DPPC/cholesterol bilayers including 40 mol% cholesterol from the liquid-ordered (LO) phase are simulated with constant NPzAT MD simulations by applying various areal strains eA, defined by the increase ratio of the area of the stretched bilayer to the un-stretched bilayer, until a pore forms (eA ∼ 1.4). From the visual inspection of snapshots obtained by MD simulations, we found the dynamics of the pore formation can be divided into four stages. In the first stage (0.0 ≤ eA ≤ 0.3), DPPC molecules become disordered monotonically. In the second stage (0.3 < eA ≤ 1.0), DPPC molecules of the two monolayers start to interdigitate in a part of the bilayer and the order of DPPC molecules are recovered slightly. This indicates the LO phase transforms to the coexisting phase of LO and an interdigitated gel (LβI) like phases. The region of the LβI-like phase grows with the increase of eA and dominates near the upper limit of this stage. In the third stage (1.0 < eA ≤ 1.2), DPPC molecules in the LβI-like phase bilayer become disordered again, and in the fourth stage (1.2 < eA ≤ 1.4), a transmembrane pore forms. The critical areal strain (∼1.4), where the pore forms, for the DPPC/cholesterol bilayer is about double of that reported for the pure DPPC bilayer previously, in qualitative agreement with corresponding experimental data. We suspect the phase transition from LO to LβI-like phase is involved into the toughness of the DPPC/cholesterol bilayer under mechanical stresses.