Application of evolutionary algorithm methods to polypeptide folding: comparison with experimental results for unsolvated Ac-(Ala-Gly-Gly)5-LysH+.

We present an evolutionary method for finding the low-energy conformations of polypeptides. The application, called FOLDAWAY,is based on a generic framework and uses several evolutionary operators as well as local optimization to navigate the complex energy landscape of polypeptides. It maintains two complementary representations of the structures and uses the CHARMM force field for evaluating the energies. The method is applied to unsolvated Met-enkephalin and Ac-(Ala-Gly-Gly)(5)-Lys(+)H(+). Unsolvated Ac-(Ala-Gly-Gly)(5)-Lys(+)H(+) has been the object of recent experimental studies using ion mobility measurements. It has a flat energy landscape where helical and globular conformations have similar energies. FOLDAWAY locates several large groups of structures not found in previous molecular dynamics simulations for this peptide, including compact globular conformations, which are probably present in the experiments. However, the relative energies of the different conformations found by FOLDAWAY do not accurately match the relative energies expected from the experimental observations.

All-atom generalized-ensemble simulations of small proteins.

We give an overview of some generalized-ensemble techniques that have proven successful in all-atom simulations of proteins. We show that these techniques enable efficient investigations of secondary structure formation and folding in peptides and small proteins. Results are presented for various alanine-based artificial peptides and a small protein, the 36-residued villin headpiece subdomain (HP-36). Our results indicate that all-atom simulations of proteins may be more restricted by the accuracy of the present energy functions than by the efficiency of the search algorithms.

Hot and solid gallium clusters: too small to melt.

A novel multicollision induced dissociation scheme is employed to determine the energy content for mass-selected gallium cluster ions as a function of their temperature. Measurements were performed for Ga(+)(n) (n=17 39, and 40) over a 90-720 K temperature range. For Ga+39 and Ga+40 a broad maximum in the heat capacity-a signature of a melting transition for a small cluster-occurs at around 550 K. Thus small gallium clusters melt at substantially above the 302.9 K melting point of bulk gallium, in conflict with expectations that they will remain liquid to below 150 K. No melting transition is observed for Ga+17.

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.

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).