Peptidic Macrocycles - Conformational Sampling and Thermodynamic Characterization

• Published in: Journal of chemical information and modeling Vol. 58; no. 5; pp. 982 - 992
• Main Authors: Kamenik, Anna S, Lessel, Uta, Fuchs, Julian E, Fox, Thomas, Liedl, Klaus R
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 29.05.2018
• Subjects: Clustering; Computer simulation; Crystallography; Free energy; Macrocyclic Compounds - chemistry; Molecular chains; Molecular chemistry; Molecular dynamics; Molecular Dynamics Simulation; NMR; Nuclear magnetic resonance; Peptides; Peptides - chemistry; Protein Conformation; Sampling; Thermodynamics
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/acs.jcim.8b00097

Macrocycles are of considerable interest as highly specific drug candidates, yet they challenge standard conformer generators with their large number of rotatable bonds and conformational restrictions. Here, we present a molecular dynamics-based routine that bypasses current limitations in conformational sampling and extensively profiles the free energy landscape of peptidic macrocycles in solution. We perform accelerated molecular dynamics simulations to capture a diverse conformational ensemble. By applying an energetic cutoff, followed by geometric clustering, we demonstrate the striking robustness and efficiency of the approach in identifying highly populated conformational states of cyclic peptides. The resulting structural and thermodynamic information is benchmarked against interproton distances from NMR experiments and conformational states identified by X-ray crystallography. Using three different model systems of varying size and flexibility, we show that the method reliably reproduces experimentally determined structural ensembles and is capable of identifying key conformational states that include the bioactive conformation. Thus, the described approach is a robust method to generate conformations of peptidic macrocycles and holds promise for structure-based drug design.