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

Abstract

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.

Slide-and-exchange mechanism for rapid and selective transport through the nuclear pore complex

“…The simulations were conducted using a complex of the NTF2 dimer (PDB 1GYB) (66), fully solvated, with the disordered FSFG 6 construct in conformations generated by a combination of FlexPepDock (80) and implicit short solvent simulation in AMBER. Simulations of other constructs were performed by modification of this starting system.…”

Understanding the challenges of protein flexibility in drug design

“…An additional challenge for on-the-fly docking relates to predicting binding modes of peptides [147]. As opposed to small drug-like ligands, large peptides have a complex dynamic behavior: they can establish intricate networks of hydrogen bonds and even fold into secondary structures [147].…”

“…As opposed to small drug-like ligands, large peptides have a complex dynamic behavior: they can establish intricate networks of hydrogen bonds and even fold into secondary structures [147]. Such folding properties are difficult to simulate using standard docking protocols.…”

“…Accordingly, the biggest claims regarding large target flexibility in docking are made using methods based on protein prediction platforms, such as Rosetta [100] or CABS [148]. Both platforms have been used for on-the-fly docking, considering peptides and large-scale conformational changes in the receptor [13], [21], [147]. Even though they involve coarse-grained representations of the protein-ligand complex, these approaches represent very innovative trends for on-the-fly docking.…”

Parallel Evolutionary Optimization Algorithms for Peptide-Protein Docking

“…It depends on number of degrees of freedom. In the case of local docking FlexPepDock (FPD) [10] protocol from the Rosetta framework was used with comparable run time.…”