Post-Docking Refinement of Peptide or Protein-RNA Complexes Using Thermal Titration Molecular Dynamics (TTMD): A Stability Insight

RNA-protein interactions drive and regulate fundamental cellular processes like transcription and translation. Despite being still limited, the growing body of structural data significantly contributes to the characterization of these interactions. However, RNA complexes involving proteins or peptides are not always available due to the structural determination challenges that this biopolymer entails. Consequently, modeling approaches like molecular docking are exploited to generate complexes relevant to structural and pharmaceutical purposes, including analysis of putative drug targets. Docking methods, despite their widespread adoption, are often hindered by limitations in scoring accuracy, which affects the ranking of the generated poses. Postdocking refining methods, including molecular dynamics (MD) approaches, have been developed to tackle this issue. Thermal Titration Molecular Dynamics (TTMD) is an enhanced sampling molecular dynamics technique that has been previously effectively applied to refine protein or RNA-small-molecule docking poses. This study presents the first application of TTMD to RNA-peptide complexes, validating this method on more complex systems and extending its applicability domain. Our findings showcase the capability of this technique to refine peptide-RNA docking poses, correctly identifying native binding modes among decoys for different pharmaceutically relevant targets.