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-totail 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 allatom 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.
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-totail 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 allatom 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. It results that the EGSCyP method provides a very complete characterization of the conformational space of small cyclic pentapeptides. -180.0 -90.0 0.0 90.0 180.0 φ (degrees) 180.0 90.0 0.0 -90.0 -180.0 ψ (degrees)The paper presents a new method for the exhaustive exploration of the conformational energy landscape of small head-to-tail cyclic peptides. The approach is based on a multilevel representation of the peptide and the use of robotics-inspired algorithms.
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