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bioRxiv · 10.1101/338483

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

Jusot, M.·Stratmann, D.·Vaisset, M.·Chomilier, J.·Cortes, J.
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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 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.\n\nO_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY\n\nThe 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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Jusot, M., Stratmann, D., Vaisset, M., Chomilier, J., Cortes, J.. 2018-06-05. Exhaustive exploration of the conformational landscape of small cyclic peptides using a robotics approach. https://doi.org/10.1101/338483

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