On the use of one-step perturbation to investigate the dependence of NOE-derived atom-atom distance bound violations of peptides upon a variation of force-field parameters.

The method of one-step perturbation can be used to predict from a single molecular dynamics simulation the values of observable quantities as functions of variations in the parameters of the Hamiltonian or biomolecular force field used in the simulation. The method is used to predict violations of nuclear overhauser effect (NOE) distance bounds measured in nuclear magnetic resonance (NMR) experiments by atom-atom distances of the NOE atom pairs when varying force-field parameters. Predictions of NOE distance bound violations between different versions of the GROMOS force field for a hexa-β-peptide in solution show that the technique works for rather large force-field parameter changes as well as for very different NOE bound violation patterns. The effect of changing individual force-field parameters on the NOE distance bound violations of the β-peptide and an α-peptide was investigated too. One-step perturbation, which in this case is equivalent to reweighting configurations, constitutes an efficient technique to predict many values of different quantities from a single conformational ensemble for a particular system, which makes it a powerful force-field development technique that easily reduces the number of required separate simulations by an order of magnitude.