Assessing intrinsic side chain interactions between i and i+4 residues in solvent-free peptides:: A combinatorial gas-phase approach

Ion mobility measurements and molecular modeling techniques have been used to survey the gas-phase structures of a series of alanine-rich peptides. The peptides, examined as [M + 2H](2+) ions, have the general forms NH2-(Ala)(7)-Xxx-(Ala)(3)-Yyy-(Ala)(3) and Ac-(Ala)(7)-Xxx-(Ala)(3)-Yyy-(Ala)(3), where residues 8 and 12 are randomized. In total, 160 different peptide ions (80 related NH2-terminated and -acetylated sequences) have been studied. Substitutions of residues 8 and 12 permit an assessment of the influence of specific interactions between residues in an adjacent helical turn. The formation of helices and globular structures in the gas phase appears to be sensitive to specific interactions between amino acid side chains. A preliminary discussion of these results in terms of what is currently known about helix formation in the gas phase and in solution is given. Overall, it appears that this combinatorial approach to studying sequence-to-structure interactions that are intrinsic to the peptide is a viable strategy for surveying trends in large numbers of sequences without interference from solvation effects.