Computer simulation studies of finite temperature conformational equilibrium in alanine-based peptides

Conformational equilibria in two poly-alanine and one lysine-doped poly-alanine peptide, [Ala(8)](+), [Ala(16)](+) and [Ac-(AAAAK)(3)A-NH2](3+), respectively, has been examined in both gas and water solution phase by computer simulation. The simulations studies were carried out using recently developed two-dimensional umbrella sampling techniques coupled to novel extended system multiple time step molecular dynamics methods. The efficiency of the latter method permitted run lengths greater than 30 ns to be used in the studies. The in vacuo simulation results are compared to recent novel gas-phase experimental studies employing drift tubes coupled to mass spectrometers (the injected-ion mobility/MS technique). Simulation studies of the peptides and neutralizing chloride anions solvated in computer water are compared to solution-phase NMR and ESR experimental work;. Solvent effects are elucidated through a comparison of in vacuo and solution-phase simulation results. Comparisons between the results generated for the three different peptides ale performed in order to assess the effect of the lysine side-chain and the position of the positive charge on peptide conformational equilibria in the two environments. The results indicate that the 3K peptide is roughly helical in a vacuum as well as in solution. The [Ala(16)](+) and [Ala(8)](+) form compact states in a vacuum in order to solvate the charge on the N-terminus. In water solution, the [Ala(16)](+) uncompacts but does not become strongly alpha-helical.