Rosetta FlexPepDock ab-initio: Simultaneous Folding, Docking and Refinement of Peptides onto Their Receptors

By Barak Raveh, Nir London, Lior Zimmerman, O. Schueler‐Furman. 2011

297 citations recorded by the source corpus.

Flexible peptides that fold upon binding to another protein molecule mediate a large number of regulatory interactions in the living cell and may provide highly specific recognition modules. We present Rosetta FlexPepDock ab-initio, a protocol for simultaneous docking and de-novo folding of peptides, starting from an approximate specification of the peptide binding site. Using the Rosetta fragments library and a coarse-grained structural representation of the peptide and the receptor, FlexPepDock ab-initio samples efficiently and simultaneously the space of possible peptide backbone conformations and rigid-body orientations over the receptor surface of a given binding site. The subsequent all-atom refinement of the coarse-grained models includes full side-chain modeling of both the receptor and the peptide, resulting in high-resolution models in which key side-chain interactions are recapitulated. The protocol was applied to a benchmark in which peptides were modeled over receptors in either their bound backbone conformations or in their free, unbound form. Near-native peptide conformations were identified in 18/26 of the bound cases and 7/14 of the unbound cases. The protocol performs well on peptides from various classes of secondary structures, including coiled peptides with unusual turns and kinks. The results presented here significantly extend the scope of state-of-the-art methods for high-resolution peptide modeling, which can now be applied to a wide variety of peptide-protein interactions where no prior information about the peptide backbone conformation is available, enabling detailed structure-based studies and manipulation of those interactions.

Subfields: Molecular Biology

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Citations in the corpus

A Unified Conformational Selection and Induced Fit Approach to Protein-Peptide Docking (2013, unknown): “When no information about the peptide backbone conformation is available, the same authors have proposed a much more computationally demanding pipeline [25] that combines Rosetta ab-initio predictions to ‘fold’ the peptide and FlexPepDock to refine the binding mode.”
Rosetta FlexPepDock web server—high resolution modeling of peptide–protein interactions (2011, methodology): “FlexPepDock ab initio performed well on a benchmark of peptide– protein interactions (38).”
A Comprehensive Review on Current Advances in Peptide Drug Development and Design (2019, methodology): “Rosetta FlexPepDock ab initio, for instance, is a protocol that combines ab initio peptide folding with local docking by placing the query peptide into a user-defined binding site from any arbitrary backbone conformation [96].”
HPEPDOCK: a web server for blind peptide–protein docking based on a hierarchical algorithm (2018, unknown): “The Rosetta FlexPepDock (13), PepCrawler (14) and HADDOCK peptide protocol (11) are well-known algorithms for local peptide-docking, where the protein–peptide binding modes were obtained through a high-resolution docking refinement within the binding site.”