Conformational Behavior of Peptides
Kinetic Models of Cyclic Peptides
Peptides and peptidomimetics have recently attracted much attention as alternative chemotypes to interfere with key therapeutic targets such as class B G-protein coupled receptors and protein-protein interactions. The preferred route for delivering drugs is oral administration, for which the compound must be able to cross the gut wall by passive diffusion. Therefore, the successful development of peptide-type drugs requires a reliable determination of the membrane permeability of molecules. As experimental assays are time and cost intensive, computational approaches are particularly appealing for this purpose.
Kinetic models based on multi-microsecond molecular dynamics data obtained in polar and apolar environments are employed to rationalize the membrane permeability of cyclic peptides. As an example the natural product cyclosporin A was used . The conformational landscape of such systems was found to be more complicated than previously assumed, and thus not only thermodynamics but also kinetics are important to understand the unusually good permeability of cyclosporin A. Due to the increased flexibility of cyclic peptides compared to small organic molecules, different conformations can exhibit largely different polarities. As a result, the interconversion rates between metastable conformational states become a determining factor for permeability.
Structural Effects of Posttranslational Modifications
Posttranslational modifications play important roles in biological systems. In the case of polytheonamide B (pTB), which is one of the most heavily posttranslationally modified biomolecules known, the N-methylation of asparagine side chains were found to be crucial to stabilize the unusual β6.3-helical fold by forming an “exoskeleton” . This channel-like function is required for the cytotoxic activity of the natural product. Reversion of the N-methylations led to a complete loss of the helical structure. Comparison with experimental data showed that the order in which the asparagine residues are N-methylated in nature parallels the build-up of the β-helical fold. The N-methylations alter the hydrogen-bonding preferences of the asparagine side chains towards intramolecular hydrogen bonds, which allows the formation of the “exoskeleton”. These findings could lead to the establishment of a general strategy to stabilise special (β-)helical conformations of engineered peptides and peptidomimetics.