Intertwined Coil Inspired Modeling of β-Barrel Membrane Protein Structures using Predicted Interstrand Interaction Constraints

Abstract

Among the two classes of membrane proteins, beta-barrel membrane proteins are found in the outer membrane of Gram-negative bacteria, mitochondria, and chloroplasts. They carry out diverse biological functions, including pore formation, membrane anchoring, enzyme activity, and are often responsible for bacterial virulence. Although membrane proteins comprise approximately one third of all proteins encoded in a genome, they are sparsely represented in the protein structure databank, due to difficulties in experimental structural determination. We have developed a computational method to predict three dimensional structures of beta-barrel membrane proteins from transmembrane sequence segments. Our method takes advantage of an asymmetric potential function derived from detailed combinatorial analysis of known membrane protein structures. In addition, we have developed a model to account for interstrand loop entropy. In a set of 25 non-homologous proteins with known structures, we can successfully predict strand register at 76% accuracy. This is a significant improvement from previous results (44%) and from random chance (7%) [1]. Based on predicted strand registrations, we are now able to predict the three dimensional structure of the transmembrane region of beta-barrel membrane proteins from sequences alone. The average RMSD of transmembrane region between predicted and native beta-barrel membrane protein structure is less than 4A° for Cα and main chain models and less than 6A° for an all atom model for this set of 25 nonhomologous proteins in a blind test. Our method is general and can be applied to genome-wide structural prediction.[1] Ronald Jackups, Jr. and Jie Liang. Interstrand pairing patterns in beta-barrel membrane proteins: the positive-outside rule, aromatic rescue, and strand registration prediction J Mol Biol. 2005, 354:979-993.