Investigation of methanol-peptide nuclear Overhauser effects through molecular dynamics simulations.

ABSTRACT

Intermolecular nuclear Overhauser effects (NOEs) produced by interactions of methanol with [val(5)]angiotensin in 25% methanol-water at 0 °C were examined through molecular dynamics (MD) simulations and compared to experimental results. Calculated average (3)J(NHCαH) spin coupling constants, conformation-sensitive chemical shift changes, and intramolecular (1)H-(1)H NOEs indicated that peptide conformations present over the course of simulation trajectories of 100-300 ns are likely similar to those present in the experimental system. Calculated cross-relaxation terms for the methanol-peptide interactions showed the same trends as corresponding experimental data but were about a factor of 3 too large. The lack of agreement between observed and calculated cross-relaxation terms probably has origins in characteristics of the simulations that lead to overestimation of translational diffusion coefficients of the system components. Simulations confirmed the heterogeneity of the methanol-water solvent at the molecular level, with clusters of methanol and water molecules changing their size and composition on a subpicosecond time scale. Most peptide hydrogens are preferentially solvated by interactions with methanol molecules. Simulations suggest that diffusion of water and methanol molecules near the peptide is slowed as these species approach the peptide backbone.