Predicting the Sequence-Dependent Backbone Dynamics of Intrinsically Disordered Proteins

Abstract

AbstractDynamics is a crucial link between sequence and function for intrinsically disordered proteins (IDPs). NMR spin relaxation is a powerful technique for characterizing the sequence-dependent backbone dynamics of IDPs. Of particular interest is the15N transverse relaxation rate (R2), which reports on slower dynamics (10s of ns up to 1 μs and beyond). NMR and molecular dynamics (MD) simulations have shown that local interactions and secondary structure formation slow down backbone dynamics and raiseR2. ElevatedR2has been suggested to be indicators of propensities of membrane association, liquid-liquid phase separation, and other functional processes. Here we present a sequence-based method, SeqDYN, for predictingR2of IDPs. TheR2value of a residue is expressed as the product of contributing factors from all residues, which attenuate with increasing sequence distance from the central residue. The mathematical model has 21 parameters, representing the correlation length (where the attenuation is at 50%) and the amplitudes of the contributing factors of the 20 types of amino acids. Training on a set of 45 IDPs reveals a correlation length of 5.6 residues, aromatic and long branched aliphatic amino acids and Arg asR2promotors whereas Gly and short polar amino acids asR2suppressors. The prediction accuracy of SeqDYN is competitive against that of recent MD simulations using IDP-specific force fields. For a structured protein, SeqDYN prediction representsR2in the unfolded state. SeqDYN is available as a web server athttps://zhougroup-uic.github.io/SeqDYNidp/for rapidR2prediction.Significance StatementHow the sequences of intrinsically disordered proteins (IDPs) code for functions is still an enigma. Dynamics, in particular residue-specific dynamics, holds crucial clues. Enormous efforts have been spent to characterize residue-specific dynamics of IDPs, mainly through NMR spin relaxation experiments. Here we present a sequence-based method, SeqDYN, for predicting residue-specific backbone dynamics of IDPs. SeqDYN employs a mathematical model with 21 parameters and is trained on 45 IDPs. It provides not only rapid, accurate prediction but also insightful physical interpretation of sequence-dependent IDP dynamics.