AFflecto: A web server to generate conformational ensembles of flexible proteins from AlphaFold models
Mátyás Pajkos, Ilinka Clerc, Christophe Zanon, Pau Bernadó, Juan Cortés
Abstract
• Many proteins consist of well-structured domains with flexible regions. • AlphaFold predicts folded domains but fails to model disordered regions. • AFflecto generates ensembles by sampling disordered regions: linkers, tails, loops. • Ensembles show flexible protein states for biophysical analyses or simulations. 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. Understanding these complex relationships is crucial for therapeutic development, highlighting the need for methods to generate plausible IDP/IDR conformational ensembles. 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/.