Abstract
Intrinsically disordered proteins and regions (IDPs/IDRs) leverage their structural flexibility to fulfill essential cellular functions, with dysfunctions often linked to severe diseases. However, the relationships between their sequences, structural dynamics and functional roles remain poorly understood. Understading these complex relationships is crucial for therapeutic development, highlighting the need for methods that generate ensembles of plausible IDP/IDR conformers. While AlphaFold (AF) excels at modeling structured domains, it fails to accurately represent disordered regions, leaving a significant portion of proteomes inaccurately modeled. We present AFflecto, a user-friendly web server for generating large conformational ensembles of proteins that include both structured domains and IDRs from AF structural models. AFflecto identifies IDRs as tails, linkers or loops by analyzing their structural context. Additionally, it incorporates a method to identify conditionally folded IDRs that AF may incorrectly predict as natively folded elements. The conformational space is globally explored using efficient stochastic sampling algorithms. AFflecto's web interface allows users to customize the modeling, by modifying boundaries between ordered and disordered regions, and selecting among several sampling strategies. The web server is freely available at https://moma.laas.fr/applications/AFflecto/.</p></div>