The energy landscape of unsolvated peptides: helix formation and cold denaturation in Ac-A4G7A4 + H+.

Ion mobility measurements and molecular dynamics simulations were performed for unsolvated A4G7A4 + H+ and Ac-A4G7A4 + H+ (Ac = acetyl, A = alanine, G = glycine) peptides. As expected, A4G7A4 + H+ adopts a globular conformation (a compact, random-looking, three-dimensional structure) over the entire temperature range examined (100-410 K). Ac-A4G7A4 + H+ on the other hand is designed to have a flat energy landscape with a marginally stable helical state. This peptide shows at least four different conformations at low temperatures (<230 K). The two conformations with the largest cross sections are attributed to - and partial -helices, while the one with the smallest cross section is globular. The other main conformation may be partially helical. Ac-A4G7A4 + H+ becomes predominantly globular at intermediate temperatures and then becomes more helical as the temperature is raised further. This unexpected behavior may be due to the helix having a higher vibrational entropy than the globular state, as predicted by some recent calculations (Ma, B.; Tsai, C.-J.; Nussinov, R. Biophys. J. 2000, 79, 2739-2753).