HYDROPHOBIC NATURE OF MEMBRANE-SPANNING ALPHA-HELICAL PEPTIDES AS REVEALED BY MONTE-CARLO SIMULATIONS AND MOLECULAR HYDROPHOBICITY POTENTIAL ANALYSIS

We propose an approach to explore the spatial hydrophobic and hydrophi lic properties of transmembrane alpha-helical peptides. The computatio nal procedure employs two independent techniques-statistical mechanics Monte Carlo (MC) simulations of nonpolar (propane) and polar (water) solvents around the peptides and three-dimensional molecular hydrophob icity potential (3D MHP) calculations. In the first approach, the pola rity of a helix exposure was analyzed in terms of the average peptide- solvent interaction energies, whereas, in the second one, it was asses sed using the 3D MHP distribution on the helix surface. The results ob tained in the frameworks of both formalisms are in reasonable agreemen t, compliment each other, and provided a detailed presentation of the spatial hydrophobic nature of the peptides. Particular emphasis was pu t on testing the validity of simulations, examination of the convergen ce of energies in the MC runs, and comparison of the hydrophobicity me asures obtained using different techniques. The method was applied to several transmembrane alpha-helical peptides from proteins with known structure. Resulting hydrophobic characteristics were compared with ex perimentally observed lipid- and protein-exposure of these segments in 3D structures of the membrane bundles. The approach was also employed in the hydrophobic mapping of putative channel-forming alpha-helical peptide in epithelial amiloride-sensitive Na+ channel, and the results obtained were used to predict the residues lining the pore as well as exposed to a nonpolar environment. Future applications of the method to spatial arrangement of alpha-helices in membrane protein domains ar e discussed.