Role of hydrophobicity and solvent-mediated charge-charge interactions in stabilizing alpha-helices

A theoretical study to identify the conformational preferences of lysine-ba sed oligopeptides has been carried out. The solvation free energy and free energy of ionization of the oligopeptides have been calculated by using a f ast multigrid boundary element method that considers the coupling between t he conformation of the molecule and the ionization equilibria explicitly, a t a given pH value. It has been found experimentally that isolated alanine and lysine residues have somewhat small intrinsic helix-forming tendencies; however, results from these simulations indicate that conformations contai ning right handed alpha-helical turns are energetically favorable at low va lues of pH for lysine-based oligopeptides. Also, unusual patterns of intera ctions among lysine side chains with large hydrophobic contacts and close p roximity (5-6 Angstrom) between charged NH3+ groups are observed. Similar a rrangements of charged groups have been seen for lysine and arginine residu es in experimentally determined structures of proteins available from the P rotein Data Bank. The lowest-free-energy conformation of the sequence Ac-(L YS)(6)-NMe from these simulations showed large pK(alpha) shifts for some of the NH3+ groups of the lysine residues. Such large effects are not observe d in the lowest-energy conformations of oligopeptide sequences with two, th ree, or four lysine residues. Calculations on the sequence Ac-LYS-(ALA)(4)- LYS-NMe also reveal low-energy alpha-helical conformations with interaction s of one of the LYS side chains with the helix backbone in an arrangement q uite similar to the one described recently by Groebke et al., 1996 (Proc. N atl. Acad. Sci. U.S.A. 93:4025-4029). The results of this study provide a s ound basis with which to discuss the nature of the interactions, such as hy drophobicity, charge-charge interaction, and solvent polarization effects, that stabilize right-handed a-helical conformations.