A Cyclisation and Docking Protocol for Cyclic Peptide-Protein Modelling using HADDOCK2.4

Charitou, Vicky; Keulen, Siri C. van; Bonvin, Alexandre M. J. J.

doi:10.1101/2022.01.21.477251

Cited by 1 publication

(1 citation statement)

References 37 publications

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“…Thus, dynamic binding effects of unbound (apo) protein states, where the conformational architecture of the binding site is significantly different from holo complexes, cannot be modeled in that way. Only recently, molecular docking studies of peptidic MCs were performed in apo structures using specialized tools for (cyclic) peptides, , emphasizing the current need for methods capable of handling these structural challenges.…”

Section: Introductionmentioning

confidence: 99%

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

Meixner

Zachmann

Metzler

et al. 2022

J. Chem. Inf. Model.

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Macrocycles are interesting molecules with unique features due to their conformationally constrained yet flexible ring structure. This characteristic poses a difficult challenge for computational modeling studies since they rely on accurate structural descriptions. In particular, molecular docking calculations suffer from the lack of ring flexibility during pose generation, which is often compensated by using pregenerated ligand conformer ensembles. Moreover, receptor structures are mainly treated rigidly, which limits the use of many docking tools. In this study, we optimized our previous molecular dynamics-based sampling and docking pipeline specifically designed for the accurate prediction of macrocyclic compounds. We developed a dihedral classification procedure for in-depth conformational analysis of the macrocyclic rings and extracted structural ensembles that were subsequently docked in both bound and unbound protein structures employing a fully flexible approach. Our results suggest that including a ring conformer close to the bound state in the starting ensemble increases the chance of successful docking. The bioactive conformations of a diverse set of ligands could be predicted with high and decent accuracy in bound and unbound protein structures, respectively, due to the incorporation of full molecular flexibility in our approach. The remaining unsuccessful docking calculations were mainly caused by large flexible substituents that bind to surface-exposed binding sites, rather than the macrocyclic ring per se and could be further improved by explicit molecular dynamics simulations of the docked complex.

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Section: Introductionmentioning

confidence: 99%