RNAtive to recognize native-like structure in a set of RNA 3D models

Abstract

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSMotivationC_ST_ABSMost widely used methods for evaluating RNA 3D structure models require experimental reference structures, which restricts their use for novel RNAs. They also often overlook recurrent structural features shared across multiple predictions of the same sequence. Although consensus approaches have proven effective in RNA sequence analysis and evolutionary studies, no existing tool applies these principles to evaluate ensembles of 3D models. This gap hampers the identification of native-like folds in computational predictions, particularly as AI-driven methods become increasingly prevalent. ResultsThis paper presents RNAtive, the first computational tool to apply consensus-derived secondary structures for reference-free evaluation of RNA 3D models. RNAtive aggregates recurrent base-pairing and stacking interactions across ensembles of predicted 3D structures to construct a consensus secondary structure. It introduces a novel conditionally weighted consensus mode that treats interaction networks as fuzzy sets and uniquely allows integration of user-defined 2D structural constraints, enabling evaluation guided by experimental data. Input RNA models are ranked using two adapted binary-classification-based scores. Benchmarking against CASP15 competition data shows that models consistent with the consensus exhibit native-like structural features. The RNAtive web server offers an intuitive platform for comparing and prioritizing RNA 3D predictions, providing a scalable solution to address the variability inherent in deep learning and fragment-assembly methods. By bridging consensus principles with 3D structural analysis, RNAtive advances the exploration of RNA conformational landscapes and has potential applications in fields like therapeutic RNA design. AvailabilityRNAtive is a freely accessible web server with a modern, user-friendly interface, available for scientific, educational, and commercial use at https://rnative.cs.put.poznan.pl/. Contacttomasz.zok@cs.put.poznan.pl