Folding of unsolvated polypeptides

High resolution ion mobility measurements and temperature-variable ion mobility measurements have been used to study the folding properties of unsolvated polypeptides. Molecular dynamics (MD) and an evolutionary algorithm (EA) were used to assist in the assignment of the features seen in the mobility spectra.; The in vacuo helix forming tendencies of aliphatic amino acids was determined by examining several valine-based and leucine-based polypeptides with up to 20 residues. Alanine- and glycine-based peptides had been studied previously. Overall, the ordering of helix-forming tendencies in unsolvated polypeptides appeared to be Val > Leu > Ala >> Gly. This is different from what was seen in aqueous solution, but parallels the helix propensities determined in polar solvents and membrane-like environments.; The conformations of unsolvated Ac-(AGG)₅K+H+ and Ac-A₄G₇A₄+H+ were examined by ion mobility measurements over a wide temperature range (150–410 K). The rate constants for the loss of helix were measured as a function of temperature for the Ac-(AGG)₅K+H+ peptide, and an Arrhenius activation energy and preexponential factor were determined. At least four different conformations were seen for the Ac-A₄G ₇A₄+H+ peptide at low temperatures. Although the interactions between these peaks were too complicated to allow kinetic analysis, it was found that the peptide becomes more helical as the temperature is raised well above room temperature. This unexpected behavior may have been due to the helical state having higher vibrational entropy than the globular state.; An evolutionary algorithm was developed to assist the MD in the finding of low energy candidate structures for assigning features in the drift spectra. The application, called FoldAway, is based on a generic evolutionary computation framework and utilizes a multitude of evolutionary operators as well as local optimization methods to navigate the complex energy surface landscape of polypeptides. To demonstrate the potential of this approach, results for the Ac-(AGG)₅K+H+ polypeptide are given and compared with molecular dynamics and experimental results. The results indicate that FoldAway is capable of exploring a much broader range of the potential energy surface than molecular dynamics, and explores a wealth of very compact structures that have been seen to be important in the experiments.