The energy landscape of unsolvated peptides: The role of context in the stability of alanine/glycine helices

Ion mobility measurements have been used to examine the conformations present for unsolvated Ac-(AG)(7)A+H+ and (AG)(7)A+H+ peptides (Ac = acetyl, A = alanine, and G = glycine) over a broad temperature range (100-410 K). The results are compared to those recently reported for Ac-A(4)G(7)A(4)+H+ and A(4)G(7)A(4)+H+, which have the same compositions but different sequences. Ac-(AG)(7)A+H+ shows less conformational diversity than Ac-A(4)G(7)A(4)+H+; it is much less helical than Ac-A(4)G(7)A(4)+H+ at the upper end of the temperature range studied, and at low temperatures, one of the two Ac-A(4)G(7)A(4)+H+ features assigned to helical conformations is missing for Ac-(AG)(7)A+H+. Molecular dynamics simulations suggest that the different conformational preferences are not due to differences in the stabilities of the helical states, but differences in the nonhelical states: it appears that Ac-(AG)(7)A+H+ is more flexible and able to adopt lower energy globular conformations (compact random looking three-dimensional structures) than Ac-A(4)G(7)A(4)+H+. The helix to globule transition that occurs for Ac-(AG)(7)A+H+ at around 250-350 K is not a direct (two-state) process, but a creeping transition that takes place through at least one and probably several intermediates.