Molecular Dynamics Simulations of Small Peptides: Can One Derive Conformational Preferences from ROESY Spectra?

Folding properties of β‐peptides were investigated by means of NMR experiments and MD simulations of β‐dipeptides, which serve as small test systems to study the influence of stereocenters and side chains on hydrogen‐bond and consequently on secondary‐structure formation. Two stereoisomers, SRand SS, of a Val‐Phe dipeptide, and of the corresponding Ala‐Ala dipeptide, and a Gly‐Gly dipeptide were simulated in methanol for 40 ns. In agreement with experiment, the isomers of the Val‐Phe dipeptide adopt quite different conformers at 298 K, the differences being reduced at 340 K. Interestingly, the SRisomer shows enhanced hydrogen bonding at the higher temperature. The adopted conformations are primarily determined by the Ror Sside chain substitution, and less by the type of side chain. Back‐calculation of 1H ROESY spectra and 3Jcoupling constants from the MD simulations and comparison with the experimental data for the Val‐Phe dipeptides shows good agreement between simulation and experiment, and reveals possible problems and pitfalls, when deriving structural properties of a small and extremely flexible molecule from NMR data only. Inclusion of all aspects of internal dynamics is essential to the correct prediction of the NMR spectra of these small molecules. Cross comparison of calculated with experimental spectra for both isomers shows that only a few out of many ROESY peaks reflect the sizeable conformational differences between the isomers at 298 K.