Abstract
We present the results of microsecond length simulations of folding for three model helix-forming peptides, penta-alanine Ac-A5-NH2 (acA5a), a modified pentapeptide Ac-WA3H+-NH2 (WH5) and a 21-residue peptide Ac-WA3H+-(AAARA)3-A-NH2 (WH21), employing three protein force fields, AMBER03, CHARMM27 and OPLS-AA. The calculated helix populations are in good agreement with observations for all peptides, and the measured kinetic rate constants of WH5 are well reproduced. Our results yield new and interesting insights into the mechanism of α-helix folding. For acA5a, representing a flexible generic helical nucleus, we find significant variation of the folding pathway with employed force field. For the WH5 helix, which includes a stabilising side chain interaction, the nucleation step also varies with force field, but an intermediate with first two hydrogen bonds formed is a common feature in all models. For WH21 the three employed force fields differed in details of the helix initiation stage. However, the main stages of folding, involving first the central region, then the N-terminal and finally the C-terminal, were very similar in AMBER03, CHARMM27 and OPLS-AA. Single-helix structures were dominant intermediates, with a minor contribution from helix-turn-helix conformers. The agreement between simulations and experimental data indicate that current protein force fields provide a reliable description α-helix folding.
Acknowledgements
We acknowledge the BU Academic and Research Computer Services for use of computer resources. This project was supported in part by Baylor internal funding for GSJ, and a Big XII summer fellowship and a sub-award for DOE grant DE-FG02-08ER46528 grant for KK.