**Bálint Mészáros 1,2,3,\*, László Dobson 4,5, Erzsébet Fichó <sup>3</sup> and István Simon 3,\***


Received: 9 October 2019; Accepted: 30 October 2019; Published: 1 November 2019

**Abstract:** Intrinsically disordered proteins mediate crucial biological functions through their interactions with other proteins. Mutual synergistic folding (MSF) occurs when all interacting proteins are disordered, folding into a stable structure in the course of the complex formation. In these cases, the folding and binding processes occur in parallel, lending the resulting structures uniquely heterogeneous features. Currently there are no dedicated classification approaches that take into account the particular biological and biophysical properties of MSF complexes. Here, we present a scalable clustering-based classification scheme, built on redundancy-filtered features that describe the sequence and structure properties of the complexes and the role of the interaction, which is directly responsible for structure formation. Using this approach, we define six major types of MSF complexes, corresponding to biologically meaningful groups. Hence, the presented method also shows that differences in binding strength, subcellular localization, and regulation are encoded in the sequence and structural properties of proteins. While current protein structure classification methods can also handle complex structures, we show that the developed scheme is fundamentally different, and since it takes into account defining features of MSF complexes, it serves as a better representation of structures arising through this specific interaction mode.

**Keywords:** intrinsically disordered protein; IDP; protein–protein interaction; mutual synergistic folding; coupled folding and binding; structural analysis; structure-based classification; fold recognition
