Temperature Replica Exchange Molecular Dynamics Simulations of Cyclic Peptide Conformation

Cyclic peptides (CPs) have applications as pharmaceuticals, agricultural chemicals, and nanomaterials. CPs often take specific, interchanging 3D structures (conformations). The activity of CPs depends on their atomic-level structures and conformational dynamics. Characterising these properties is important to a fundamental understanding of CP function but has historically proven difficult.

Molecular dynamics simulations (MDS) represent each atom of the system of interest explicitly and propagate each atom with Newtonian dynamics. MDS allow characterisation of 3D structures of molecules like CPs with atomic-level and femtosecond-level detail. However, systems simulated using conventional MDS can become stuck in free energy minima (Fig. 1), meaning that they are challenged in capturing long-timescale (microsecond and above) CP conformational changes.

A special kind of MDS, temperature replica exchange MDS (TREMDS), have increasingly been used to study CPs. TREMDS have the advantage of maintaining the atomic-level detail of MDS and capturing long-timescale peptide conformational changes. TREMDS involve concurrently running a series of MDS at various temperatures and swapping between them every so often, allowing enhanced conformational sampling at the lower temperature of interest compared with MDS (Fig. 1). TREMDS are publicly available within several MDS engines, including GROMACS, GENESIS, CHARMM, and NAMD. We note that other kinds of replica exchange MDS also exist; for example, see refs.

Several studies have reported the remarkable accuracy of TREMDS in the structure prediction of CPs. Geng et al. conducted TREMDS of 20 CPs with known crystal structures.[13] Depending on the simulation parameters (i.e. ‘force fields’), approximately half to 15 of the CP crystal structures were predicted by TREMDS with subangstrom accuracy. A separate TREMDS study by Hu et al. found that the most populated conformation observed in the TREMDS of Ac–(cyclo-1,5)-[CAAIS5(2-Me)(R)]–NH2 (S5, (S)-pentenylglycine) was ‘almost identical to its solved structure.’ Zhao et al. calculated the 3JNHCHa couplings and NOEs from TREMDS simulations of Ac–cyclo(Asp–Ala–Ala–Dap)–Ala–Ala–NH2 and Ac–cyclo(iso-Asp–Ala–Ala–Dap)–Ala–Ala]–NH2 (Dap, 2,3-diaminopropionic acid); these agreed with NMR measurements.