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Exhaustive Exploration of the Conformational Landscape of Small Cyclic Peptides Using a Robotics Approach

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Small cyclic peptides represent a promising class of therapeutic molecules with unique chemical properties. However, the poor knowledge of their structural characteristics makes their computational design and structure prediction a… Click to show full abstract

Small cyclic peptides represent a promising class of therapeutic molecules with unique chemical properties. However, the poor knowledge of their structural characteristics makes their computational design and structure prediction a real challenge. In order to better describe their conformational space, we developed a method, named EGSCyP, for the exhaustive exploration of the energy landscape of small head-to-tail cyclic peptides. The method can be summarized by (i) a global exploration of the conformational space based on a mechanistic representation of the peptide and the use of robotics-based algorithms to deal with the closure constraint and (ii) an all-atom refinement of the obtained conformations. EGSCyP can handle D-form residues and N-methylations. Two strategies for the side-chains placement were implemented and compared. To validate our approach, we applied it to a set of three variants of cyclic RGDFV pentapeptides, including the drug candidate Cilengitide. A comparative analysis was made with respect to replica exchange molecular dynamics simulations in implicit solvent. Its results show that the EGSCyP method provides a very complete characterization of the conformational space of small cyclic pentapeptides.

Keywords: landscape small; small cyclic; robotics; exhaustive exploration; cyclic peptides

Journal Title: Journal of chemical information and modeling
Year Published: 2018

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