The structural states of proteins include ordered globular domains as well as intrinsically disordered protein regions that exist as highly flexible conformational ensembles in isolation. Various computational tools have been developed to discriminate ordered and disordered segments based on the amino acid sequence. However, properties of IDRs can also depend on various conditions, including binding to globular protein partners or environmental factors, such as redox potential. These cases provide further challenges for the computational characterization of disordered segments. In this work we present IUPred2A, a combined web interface that allows to generate energy estimation based predictions for ordered and disordered residues by IUPred2 and for disordered binding regions by ANCHOR2. The updated web server retains the robustness of the original programs but offers several new features. While only minor bug fixes are implemented for IUPred, the next version of ANCHOR is significantly improved through a new architecture and parameters optimized on novel datasets. In addition, redox-sensitive regions can also be highlighted through a novel experimental feature. The web server offers graphical and text outputs, a RESTful interface, access to software download and extensive help, and can be accessed at a new location: http://iupred2a.elte.hu.

Many disordered proteins function via binding to a structured partner and undergo a disorder-to-order transition. The coupled folding and binding can confer several functional advantages such as the precise control of binding specificity without increased affinity. Additionally, the inherent flexibility allows the binding site to adopt various conformations and to bind to multiple partners. These features explain the prevalence of such binding elements in signaling and regulatory processes. In this work, we report ANCHOR, a method for the prediction of disordered binding regions. ANCHOR relies on the pairwise energy estimation approach that is the basis of IUPred, a previous general disorder prediction method. In order to predict disordered binding regions, we seek to identify segments that are in disordered regions, cannot form enough favorable intrachain interactions to fold on their own, and are likely to gain stabilizing energy by interacting with a globular protein partner. The performance of ANCHOR was found to be largely independent from the amino acid composition and adopted secondary structure. Longer binding sites generally were predicted to be segmented, in agreement with available experimentally characterized examples. Scanning several hundred proteomes showed that the occurrence of disordered binding sites increased with the complexity of the organisms even compared to disordered regions in general. Furthermore, the length distribution of binding sites was different from disordered protein regions in general and was dominated by shorter segments. These results underline the importance of disordered proteins and protein segments in establishing new binding regions. Due to their specific biophysical properties, disordered binding sites generally carry a robust sequence signal, and this signal is efficiently captured by our method. Through its generality, ANCHOR opens new ways to study the essential functional sites of disordered proteins.

Summary: ANCHOR is a web-based implementation of an original method that takes a single amino acid sequence as an input and predicts protein binding regions that are disordered in isolation but can undergo disorder-to-order transition upon binding. The server incorporates the result of a general disorder prediction method, IUPred and can carry out simple motif searches as well.Availability: The web server is available at http://anchor.enzim.hu. The program package is freely available for academic users.Contact: zsuzsa@enzim.hu

No abstract