Molecular Dynamics Simulations of the BM2 Proton Channel: Interactions with Lipids and Detergents

Abstract

Influenza viruses A and B contain M2 proton channels (A/M2 and BM2 respectively) that are vital for viral replication. Despite performing similar roles, A/M2 and BM2 have little sequence similarity, apart from a common HxxxW motif thought to be responsible for the pH-dependent channel gating. The A/M2 TM domain has been extensively studied, both experimentally and computationally. It is structurally well-characterized with several structures of the TM domain deposited in the Protein Data Bank. The structures were solved under various conditions using a range of techniques and show that the A/M2 channel exists in multiple conformations. The only structure of BM2 available is the recently-determined solution NMR structure of the full length BM2 protein (PDB id 2KIX); the first full length proton channel structure to be determined. It is structurally of interest as it was shown to form a coiled-coil tetramer. We have performed a series of atomistic Molecular Dynamics simulations of the BM2 TM domain (residues 1-33) under a range of conditions. The structure and dynamics of the channel are compared in a lipid bilayer environment and in detergent micelles (including 1,2-dihexanoyl phosphocholine, the detergent used in the solution NMR study). These studies allow us to identify key lipid-/detergent-protein interactions and compare the structural plasticity of BM2 to that of A/M2. A further aspect of these simulations is the unbiased formation of membrane protein-detergent complexes (PDCs). Membrane proteins are generally studied in detergent environments. However, relatively little is known about these PDCs. These simulations provide further information about the distribution, interactions and dynamics of detergent molecules within the PDC.