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-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.

Conformational Control of Macrocycles by Remote Structural Modification

“…92,93 Newer kinematics-based algorithms can characterize the conformational energy landscape more accurately. 94 Application of modern MM force field-based methods with enhanced sampling techniques such as meta-dynamics, replica exchange MD, accelerated MD, and low mode MD show highly promising results for characterization of structural ensembles and the energy surfaces accessible to a macrocycle. 95−97 Particularly exciting is the utility of these new methods for accurate evaluation of energy maxima and the corresponding barriers to conformational interconversion.…”

Conformation and Permeability: Cyclic Hexapeptide Diastereomers

“…11−14 Although these methods are generally used, exchange rate optimization is required for REMD simulations, and many collective variables are required for MetaD simulations. Other approaches were used to determine cyclic peptide conformations, including the following: CANDLE 18 (which combines molecular dynamics and quantum mechanics), BRIKARD 19 (which is an inverse kinematics method), and EGSCyP 20 (which is a robotics-based method).…”

Dynamic Docking of Macrocycles in Bound and Unbound Protein Structures with DynaDock

“…13 These include stochastic algorithms, where the MC ring is broken, the linear parts are sampled, and fused back together; 14,15 distance geometry, 16,17 generic shapes, 18 and knowledge-based algorithms, 19,20 as well as inverse kinematics approaches. 21,22 Furthermore, deterministic methods can be used for conformational sampling, e.g., performing molecular dynamics (MD) simulations, usually at elevated temperatures, compensating the increased interconversion barrier. 23 Approaches based on metadynamics for conformer generation (and subsequent docking) have been explored in a case study 26 and more recently investigated in benchmark studies.…”