Binding Site Identification and Flexible Docking of Single Stranded RNA to Proteins Using a Fragment-Based Approach

Abstract

Protein-RNA docking is hampered by the high flexibility of RNA, and particularly single-stranded RNA (ssRNA). Yet, ssRNA regions typically carry the specificity of protein recognition. The lack of methodology for modeling such regions limits the accuracy of current protein-RNA docking methods. We developed a fragment-based approach to model protein-bound ssRNA, based on the structure of the protein and the sequence of the RNA, without any prior knowledge of the RNA binding site or the RNA structure. The conformational diversity of each fragment is sampled by an exhaustive RNA fragment library that was created from all the existing experimental structures of protein-ssRNA complexes. A systematic and detailed analysis of fragment-based ssRNA docking was performed which constitutes a proof-of-principle for the fragment-based approach. The method was tested on two 8-homo-nucleotide ssRNA-protein complexes and was able to identify the binding site on the protein within 10 Å. Moreover, a structure of each bound ssRNA could be generated in close agreement with the crystal structure with a mean deviation of ~1.5 Å except for a terminal nucleotide. This is the first time a bound ssRNA could be modeled from sequence with high precision.

Fast and accurate grid representations for atom‐based docking with partner flexibility

“…Grid representations have been added as the default option for the ATTRACT web interface [22] and have been applied in several studies: protein-protein docking, [46] protein-peptide docking, [47] protein-RNA docking, [48,49] and simultaneous multibody docking. [28] We see no reason why grid representations would be fundamentally limited to ATTRACT: other atombased docking methods such as HADDOCK, [10,13] Swarm-Dock, [12] or RosettaDock [11] or a flexible refinement method such as FiberDock [35] could equally benefit from them.…”

“…[45] The grid representation has been implemented in ATTRACT and has already been used in protein-protein docking, [22,46] protein-peptide docking, [47] and protein-RNA docking. [48,49] The ATTRACT source code, including the grid representation routines, is freely available at www. attract.ph.tum.de.…”

MCSS-based Predictions of Binding Mode and Selectivity of Nucleotide Ligands

“…More recently, an FBD approach was applied using multi-residues fragments corresponding to 8-mers to avoid the high degrees of freedom to manage for the conformational sampling of long peptides (19). A similar approach was applied to RNA ligands using trinucleotides to predict the binding mode of singlestranded RNAs to proteins (20,21). In both cases, peptide or RNA ligands, the sequence of the oligomer is used as input for modeling the ligand-protein complex in order to reproduce known protein-ligand interactions.…”

Identification of target candidate in Polycystic ovarian syndrome and invitro evaluation of therapeutic activity of the designed RNA Aptamer

“…Refinement of docking results for their chain forming poses minimized the difficulty of designing an aptamer (24). Fragment based approach was adopted for competent docking with protein (25). This methodology is unusual and has numerous advantages over conventional rigid based docking (25) .PatchDock, an freeware for effective protein protein docking using transformation (26).…”

“…Fragment based approach was adopted for competent docking with protein (25). This methodology is unusual and has numerous advantages over conventional rigid based docking (25) .PatchDock, an freeware for effective protein protein docking using transformation (26). Based on the global binding energy, FireDock refines the docking result as top 10 proteins.…”