Predicting the Sequence-Dependent Backbone Dynamics of Intrinsically Disordered Proteins

Abstract

Dynamics 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 the ¹⁵N transverse relaxation rate ( R ₂), 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 raise R ₂. Elevated R ₂ has 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 predicting R ₂ of IDPs. The R ₂ value 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 as R ₂ promotors whereas Gly and short polar amino acids as R ₂ suppressors. The prediction accuracy of SeqDYN is competitive against that of recent MD simulations using IDP-specific force fields. For a structured protein, SeqDYN prediction represents R ₂ in the unfolded state. SeqDYN is available as a web server at https://zhougroup-uic.github.io/SeqDYNidp/ for rapid R ₂ prediction.