Prediction of membrane protein orientation in lipid bilayers: a theoretical approach

Over the past few years, several three-dimensional (3-D) structures of membrane proteins have been described with increasing accuracy, but their relationship with membranes are still not well understood. Recently, we have developed an empirical method, Integral Membrane Protein and Lipid Association (IMPALA), to predict the insertion of molecules (lipids, drugs) into lipid bilayers (Proteins 30 (1998) 357). The IMPALA uses a Monte Carlo minimisation procedure to calculate the depth and the angle of insertion of membrane-interacting molecules taking into account the restraints dictated by a lipid bilayer. In this paper, we use IMPALA to test the insertion of 23 integral membranous proteins (IMPs) and 2 soluble proteins into membranes. Four IMP are studied in detail: OmpA, maltoporin, MsCl channel and bacteriorhodopsin. The 3-D structures of the proteins are kept constant and the insertion into membrane is monitored by minimising the value of the restraint representing the sum of two terms, one for lipid perturbation and the other for hydrophobicity. The two soluble proteins are rejected from the membrane whereas, under the same conditions, all the membrane proteins remain inside, if the solvent accessible surface of the amino acids located inside the pore of porins is ignored. The results give the tilt angle of the IMP helices or strands with respect to the membrane surface and the depth of the protein mass centre insertion. We conclude that the restraint terms of IMPALA could be used to study the insertion of model structures or complexes of proteins within membranes. (C) 2001 Elsevier Science Inc. All rights reserved.