Sequence-Dependent Correlated Segments in the Intrinsically Disordered Region of ChiZ.

Alan Hicks,Cristian Escobar,Timothy Cross,Huan-Xiang Zhou

doi:10.3390/biom10060946

Abstract

How sequences of intrinsically disordered proteins (IDPs) code for their conformational dynamics is poorly understood. Here, we combined NMR spectroscopy, small-angle X-ray scattering (SAXS), and molecular dynamics (MD) simulations to characterize the conformations and dynamics of ChiZ1-64. MD simulations, first validated by SAXS and secondary chemical shift data, found scant α-helices or β-strands but a considerable propensity for polyproline II (PPII) torsion angles. Importantly, several blocks of residues (e.g., 11–29) emerge as “correlated segments”, identified by their frequent formation of PPII stretches, salt bridges, cation-π interactions, and sidechain-backbone hydrogen bonds. NMR relaxation experiments showed non-uniform transverse relaxation rates (R2s) and nuclear Overhauser enhancements (NOEs) along the sequence (e.g., high R2s and NOEs for residues 11–14 and 23–28). MD simulations further revealed that the extent of segmental correlation is sequence-dependent; segments where internal interactions are more prevalent manifest elevated “collective” motions on the 5–10 ns timescale and suppressed local motions on the sub-ns timescale. Amide proton exchange rates provides corroboration, with residues in the most correlated segment exhibiting the highest protection factors. We propose the correlated segment as a defining feature for the conformations and dynamics of IDPs.

Highlights

Disordered proteins (IDPs) and proteins containing intrinsically disordered regions (IDRs) comprise up to 40% of the proteomes in all life forms [1]
molecular dynamics (MD) simulations recapitulated these observations and suggest that the reason for the non-uniform dynamics is the formation of correlated segments, which are stabilized by polyproline II (PPII) stretches, salt bridges, cation–π interactions, and sidechain–backbone hydrogen bonds
It is becoming evident that conformational dynamics play crucial roles in the functionality of Intrinsically disordered proteins (IDPs)

Summary

Introduction

Disordered proteins (IDPs) and proteins containing intrinsically disordered regions (IDRs) comprise up to 40% of the proteomes in all life forms [1]. They are involved in numerous cellular functions, including regulation and signaling [2,3]. While lacking defined tertiary structures, IDPs can exhibit conformational preferences, such as transient secondary structures and recurrent residue–residue contacts (e.g., salt bridges and cation-π interactions) [6,7]. The conformations and dynamics of IDPs are crucial for their cellular functions. How these properties are coded by the amino acid sequences of IDPs is poorly understood.

Methods

Results

Discussion

Conclusion