PaFlexPepDock: Parallel Ab-Initio Docking of Peptides onto Their Receptors with Full Flexibility Based on Rosetta

Abstract

Structural information related to protein–peptide complexes can be very useful for novel drug discovery and design. The computational docking of protein and peptide can supplement the structural information available on protein–peptide interactions explored by experimental ways. Protein–peptide docking of this paper can be described as three processes that occur in parallel: ab-initio peptide folding, peptide docking with its receptor, and refinement of some flexible areas of the receptor as the peptide is approaching. Several existing methods have been used to sample the degrees of freedom in the three processes, which are usually triggered in an organized sequential scheme. In this paper, we proposed a parallel approach that combines all the three processes during the docking of a folding peptide with a flexible receptor. This approach mimics the actual protein–peptide docking process in parallel way, and is expected to deliver better performance than sequential approaches. We used 22 unbound protein–peptide docking examples to evaluate our method. Our analysis of the results showed that the explicit refinement of the flexible areas of the receptor facilitated more accurate modeling of the interfaces of the complexes, while combining all of the moves in parallel helped the constructing of energy funnels for predictions.

Coarse-Grained Protein Models and Their Applications

“…501−503 The coarse-grained strategies are considered promising alternatives for the future implementation of large-scale protein flexibility into on-the-fly docking (explicit flexibility) algorithms. 445,504 Such trends are represented by two methods based on Rosetta 104 and CABS 72 coarse-grained models that allow for significant structural changes during on-the-fly protein-peptide docking 213,214,383,505,506 (see Figure 8). …”

Understanding the challenges of protein flexibility in drug design

“…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.…”

Protein-peptide molecular docking with large-scale conformational changes: the p53-MDM2 interaction

“…This problem can be overcome by reducing the level of protein representation from all-atom to coarse-grained8. Rosetta9 and CABS-dock10 coarse-grained-based methods now appear to be the most effective tools that allow for large-scale protein motions during explicit peptide docking111213, as outlined in the recent review on protein flexibility in drug design2.…”