Biomolecular spin relaxation processes, such as the NOE, are commonly modeled by rotational -tumbling combined with fast motions on the sub- timescale. Motions on the supra- timescale, in contrast, are considered to be completely decorrelated to the molecular tumbling and therefore invisible. Here, we show how supra- dynamics can nonetheless influence the NOE build-up between methyl groups. This effect arises because supra- motions can cluster the fast-motion ensembles into discrete states, affecting distance averaging as well as the fast-motion order parameter and hence the cross-relaxation rate. We present a computational approach to estimate methyl–methyl cross-relaxation rates from extensive () all-atom molecular dynamics (MD) trajectories on the example of the 723-residue protein Malate Synthase G. The approach uses Markov state models (MSMs) to resolve transitions between metastable states and thus to discriminate between sub- and supra- conformational exchange. We find that supra- exchange typically increases NOESY cross-peak intensities. The methods described in this work extend the theory of modeling sub- dynamics in spin relaxation and thus contribute to a quantitative estimation of NOE cross-relaxation rates from MD simulations, eventually leading to increased precision in structural and functional studies of large proteins.