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

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 ？. Moreover, a structure of each bound ssRNA could be generated in close agreement with the crystal structure with a mean deviation of ~1.5 ？ except for a terminal nucleotide. This is the first time a bound ssRNA could be modeled from sequence with high precision.