Biophysics of Transmembrane Pores - Interactions by Coarse-Grained Molecular Dynamics Simulation

Abstract

The hydrophobic thickness of lipid bilayers has been shown to influence the biological activity of transmembrane (TM) pores which are of central importance to the biology of cells and to a number of nanotechnological applications. Here we report on a systematic exploration of protein pores and their interactions with lipid bilayers via coarse-grained molecular dynamics (CG-MD) simulation. Until recently computational studies on these interactions have focused on simplified models. To extend to a wider range of more biologically representative models of TM pores and their interactions with lipid bilayers, CG-MD simulations were employed to initially study a set of 72 pore-lipid bilayer systems. Both main structural classes of membrane proteins (alpha-helical and beta-barrel) were represented by the eight pores investigated and the nine bilayer systems (phosphate-phosphate distances: 2.8 - 5.3 nm) sample a wide range of local hydrophobic mismatch conditions. Lipid bilayer perturbation due to pore insertion, the dependence between hydrophobic mismatch and the observed pore tilt angle, and the local de-mixing of lipid types around a pore in mixed-lipid bilayers were all analysed. The local lipid bilayer perturbation caused by the inserted pores suggests possible mechanisms for both lipid bilayer-induced protein clustering and protein-induced lipid de-mixing - both driven by the hydrophobic mismatch. This has been further investigated by a series of CG-MD simulations of multiple TM pores in large planar lipid bilayer patches. To study the impact of membrane curvature on protein-lipid interactions, analogous simulations with vesicles (diameter: 31 nm) are currently being conducted.