Steric effects on intramolecular reactivity in cyclic dipeptides: Conformational analysis validated by a combined MD/DFT approach

The present Molecular Dynamics (MD) simulation study addresses the geometric requirements of close-contact formation in short peptides. This process, that is probed herein by intramolecular H-atom transfer, initiated by triplet-excited ketones, demands close contact between the H-donating and H-accepting moieties. Thus, any deduction about the compound’s reactivity based just on MD simulations, requires independent verification of the computed conformational preferences. In this study, a procedure was developed using diketopiperazine-linked benzophenone/tyrosine dyads. Specifically, it involves a comparison of the dyads’ experimental 3J(Hα–Hβ(a/b)) spin–spin coupling constants with the theoretical values obtained by weighting DFT-computed spin–spin coupling constants with the MD-computed probability distributions for the dyads’ configurations.