Simulation of the packing of idealized transmembrane alpha-helix bundles

The aim of this study is to investigate if the packing motifs of native tra nsmembrane helices can be produced by simulations with simple potentials an d to develop a method for the rapid generation of initial candidate models for integral membrane proteins composed of bundles of transmembrane helices . Constituent residues are mapped along the helix axis in order to maintain the amino acid sequence-dependent properties of the helix. Helix packing i s optimized according to a semi-empirical potential mainly composed of four components: a bilayer potential, a crossing angle potential, a helix dipol e potential and a helix-helix distance potential. A Monte Carlo simulated a nnealing protocol is employed to optimize the helix bundle system. Necessar y parameters are derived from theoretical studies and statistical analysis of experimentally determined protein structures. Preliminary testing of the method has been conducted with idealized seven Ala(20) helix bundles. The structures generated show a high degree of compactness. It was observed tha t both bacteriorhodopsin-like and delta-endotoxin-like structures are gener ated in seven-helix bundle simulations, within which the composition varies dependent upon the cooling rate. The simulation method has also been emplo yed to explore the packing of N = 4 and N = 12 transmembrane helix bundles. The results suggest that seven and 12 transmembrane helix bundles resembli ng those observed experimentally (e.g., bacteriorhodopsin, rhodopsin and cy tochrome c oxidase subunit I) may be generated by simulations using simple potentials.