Speaker: Prof Roy Johnston, School of Chemistry, University of Birmingham
Abstract: Cyclic peptides have properties that make them useful for several applications and there are many examples with antimicrobial, anticancer or other biological activities. A large library of cyclic peptides can be made from the same synthetic routes, which makes them a good system for medicinal chemists. Cyclic peptides are also very stable because they are not broken down by exopeptidases, which digest peptides starting from the termini . The constraints of cyclisation give cyclic peptides different conformational preferences to acyclic peptides. The peptide groups in acyclic peptides have a strong preference for a trans conformation, but, as the size of the ring in cyclic peptides decreases the cis isomers become more stable, with cyclic di- and tripeptides preferring all-cis conformations.
In this lecture, I will describe a detailed study of the energy landscapes of cyclic peptides [1] using the discrete path sampling method [2] in PATHSAMPLE to map the networks of minima and transition states, modelled by the AMBER ff03 force field and found using a combination of Basin Hopping Monte Carlo global optimisation and Nudged Elastic Band methods. The potential and free energy landscapes are visualised as disconnectivity graphs [3], where minima are connected by nodes representing the highest transition state on the lowest pathway between them.
I will also present the results of a recent combined computational and experimental study of the conformational behaviour of cyclic tetra-alpha/beta-peptides [4]. Discrete path sampling calculations on cyclo-[(beta -AlaGly)2] show show a very strong preference for conformations containing all trans peptide groups. For the proline-containing peptides cyclo-[Probeta -AlaAlaeta -Ala] and cyclo-[Probeta -AlaValbeta -Ala], the energy landscapes show that the most stable isomers containing cis and trans beta -Ala-Pro have similar free energies and are separated by barriers of approximately 15 kcal mol−1. NMR spectroscopy of cyclo-[Probeta -AlaLysbeta -Ala] shows the presence of conformers that do not interconvert at temperatures up to 80◦C. Calculated CD spectra for the major isomer of cyclo-[Probeta -AlaAlabeta -Ala] are in good agreement with the experimental spectra of cyclo-[Probeta -AlaLysbeta -Ala].
[1] M. T. Oakley and R. L. Johnston, J. Chem. Theory Comput., 2013, 9, 650-657. [2] D. J. Wales, Mol. Phys., 2002, 100, 3285-3305. [3] O. M. Becker and M. Karplus, J. Chem. Phys, 1997, 106, 1495-1517. [4] M. T. Oakley, E. Oheix, A. F. A. Peacock and R. L. Johnston (submitted).