CHANNELS FORMED BY THE TRANSMEMBRANE HELIX OF PHOSPHOLAMBAN - A SIMULATION STUDY

Phospholamban is a small membrane protein which can form cation select ive ion channels in lipid bilayers. Each subunit contains a single, la rgely hydrophobic transmembrane helix, The helices are thought to asse mble as a pentameric and approximately parallel bundle surrounding a c entral pore. A model of this assembly (PDB code LPSL) has been used as the starting point for molecular dynamics (MD) simulations of a syste m consisting of the pentameric helix bundle, plus 217 water molecules located within and at either mouth of the pore. Interhelix distance re straints were employed to maintain the integrity of the helix bundle d uring a 500 ps MD simulation. Water molecules within the pore exhibite d reduced diffusional and rotational mobility, Interactions between th e alpha-helix dipoles and the water dipoles, the latter aligned anti-p arallel to the former, contribute to the stability of the system. Anal ysis of the potential energy of interaction of a K+ ion as it was move d through the pore suggested that unfavourable interactions of the cat ion with the aligned helix dipoles at the N-terminal mouth were overco me by favourable ion-water interactions. Comparable analysis for a Cl ion revealed that the ion-(pore + water) interactions were unfavourabl e along the whole of the pore, increasingly so from the N- to the C-te rminal mouth. Overall, the interaction energy profiles were consistent with a pore selective for cations over anions. Pore radius profiles w ere used to predict a channel conductance of 50 to 70 ps in 0.2 M KCl, which compares well with an experimental value of 100 ps. (C) 1997 El sevier Science B.V.