Computer simulation studies of trishomocubane heptapeptide of the type Ac-Ala₃-Tris-Ala₃-NHMe

As part of an extension on the cage peptide chemistry, the present work involves an assessment of the conformational profile of trishomocubane heptapeptide of the type Ac-Ala₃-Tris-Ala₃-NHMe using molecular dynamics (MD) simulations. All MD protocols were explored within the framework of a molecular mechanics approach using the PARM94 force field parameters modified in-house to mimic the implicit and explicit solvent conditions. The 50 ns MD trajectories revealed a tendency of the trishomocubane polypeptide to adopt bent conformations in vacuo, MEOH and TIP3P solvent models, consistent with previous studies undertaken in our laboratory. The aim of this paper is to exemplify the tendency of the highly constrained cage residues to promote reverse-turn characteristics in the polypeptide chains, which could play a pivotal role in the design of new cage peptidomimetics.