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Exhaustive exploration of the conformational landscape of small cyclic peptides using a robotics approach

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, (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 1 analysis was made with respect to replica exchange molecular dynamics simulations in implicit solvent. It results that the EGSCyP method provides a very complete characterization of the conformational space of small cyclic pentapeptides.
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Submitted on : Thursday, October 11, 2018 - 4:36:44 PM
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Maud Jusot, Dirk Stratmann, Marc Vaisset, Jacques Chomilier, Juan Cortés. Exhaustive exploration of the conformational landscape of small cyclic peptides using a robotics approach. Journal of Chemical Information and Modeling, American Chemical Society, 2018, 58 (11), pp.2355-2368. ⟨10.1021/acs.jcim.8b00375⟩. ⟨hal-01893751⟩



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