Two decades of advances in sequence-based prediction of MoRFs, disorder-to-order transitioning binding regions.

Introduction: Molecular recognition features (MoRFs) are regions in protein sequences that undergo induced folding upon binding partner molecules. MoRFs are common in nature and can be predicted from sequences based on their distinctive sequence signatures.

Areas covered: We overview 20 years of progress in the sequence-based prediction of MoRFs which resulted in the development of 25 predictors of MoRFs that interact with proteins, peptides, and lipids. These methods range from simple discriminant analysis to sophisticated deep transformer networks that use protein language models. They generate relatively accurate predictions as evidenced by the results of a recently published community-driven assessment.

Expert opinion: MoRFs prediction is a mature field of research that is poised to continue at a steady pace in the foreseeable future. We anticipate further expansion of the scope of MoRF predictions to additional partner molecules, such as nucleic acids, and continued use of recent machine learning advances. Other future efforts should concentrate on improving availability of MoRF predictions by releasing, maintaining, and popularizing web servers and by depositing MoRF predictions to large databases of protein structure and function predictions. Furthermore, accurate MoRF predictions should be coupled with the equally accurate prediction and modeling of the resulting structures of complexes.