A computational approach to utilize the overlapping NOE cross-peak intensities of multiple configurational isomers (e.g., cis/trans isomerization about substituted amide bonds in peptides or proteins) is illustrated. The method, overlap ensemble dynamics, utilizes an ensemble containing the appropriate ratio of the configurational isomers. The NOE intensities, containing contributions from different isomers, are then used as a constraining function to the entire ensemble. In this manner, NOE cross-peaks which before had to be ignored can now be readily used in the computation-based structural refinement. This method should find widespread use given the large number of small molecules of pharmaceutical and medicinal interest with substituted amides and multiple configurational isomers in their NMR spectra.