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Effect of Charge Distribution on the Dynamics of Polyampholytic Disordered Proteins.

ABSTRACT: The stability and physiological function of many biomolecular coacervates depend on the structure and dynamics of intrinsically disordered proteins (IDPs) that typically contain a significant fraction of charged residues. Although the effect of relative arrangement of charged residues on IDP conformation is a well-studied problem, the associated changes in dynamics are far less understood. In this work, we systematically interrogate the effects of charge distribution on the chain-level and segmental dynamics of polyampholytic IDPs in dilute solutions. We study a coarse-grained model polyampholyte consisting of an equal fraction of two oppositely charged residues (glutamic acid and lysine) that undergoes a transition from an ideal chain-like conformation for uniformly charge-patterned sequences to a semi-compact conformation for highly charge-segregated sequences. Changes in the chain-level dynamics with increasing charge segregation correlate with changes in conformation. The chain-level and segmental dynamics conform to simple homopolymer models for uniformly charge-patterned sequences but deviate with increasing charge segregation, both in the presence and absence of hydrodynamic interactions. We discuss the significance of these findings, obtained for a model polyampholyte, in the context of a charge-rich intrinsically disordered region of the naturally occurring protein LAF-1. Our findings have important implications for understanding the effects of charge patterning on the dynamics of polyampholytic IDPs in dilute conditions using polymer scaling theories.

SUBMITTER: Devarajan DS

PROVIDER: S-EPMC10798675 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Effect of Charge Distribution on the Dynamics of Polyampholytic Disordered Proteins.

Devarajan Dinesh Sundaravadivelu DS Rekhi Shiv S Nikoubashman Arash A Kim Young C YC Howard Michael P MP Mittal Jeetain J

Macromolecules 20221012 20

The stability and physiological function of many biomolecular coacervates depend on the structure and dynamics of intrinsically disordered proteins (IDPs) that typically contain a significant fraction of charged residues. Although the effect of relative arrangement of charged residues on IDP conformation is a well-studied problem, the associated changes in dynamics are far less understood. In this work, we systematically interrogate the effects of charge distribution on the chain-level and segme ...[more]

PMID: 38250712

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Project description:The dynamics of two proteins of similar size, the globular lysozyme and the intrinsically disordered Huntingtin interacting protein, has been simulated in three states resembling a globule, a pre-molten globule, and a molten globule. A coherence time τ has been defined, measuring the delay in the display of a stochastic behaviour after a perturbation of the system. This time has been computed for two sets of collective variables: the projection of the phase point onto the positions and momenta subspaces (τ r and τ p ), and the principal components (PCs) of positions q and momenta π produced by a covariance analysis in these subspaces (τ q and τ π ). In all states τ p ≈ 3.5τ r , and τ π ≈ 3.5τ q . The coherence times of individual PCs, τ (l) q and τ (l) π, have also been computed, and τ (l) π > τ (l) q in all states. The prevalence of τ p over τ r , or of τ π over τ q , drives the dynamics of the protein over a time range of ≈1-2 ps; moreover, a hidden synchronism appears to raise the momenta subspace's coherence above that of its individual PCs. In the transition of lysozyme to the molten globule the τ (l) q decrease but, unexpectedly, the τ (l) π increase; after this transition τ p ≈ 5τ r and τ π ≈ 5τ q . A gain of kinetic coherence accompanies thus the loss of structural coherence caused by the denaturation of the protein in the transition from globule to molten globule. The increase of the τ (l) π does not take place in the analogous transition of the Huntingtin protein. These results are compared with those of a similar analysis performed on three pseudo-proteins designed by scrambling the primary sequence of the Huntingtin interacting protein, and on two oligopeptides. The hidden synchronism appears to be a generic property of these polypeptides. The τ (l) π spectrum is similar in denaturated and in intrinsically disordered biomolecules; but the gain of kinetic coherence as a result of denaturation seems to be a specific property of the biologically functional lysozyme.

Dataset Information

Effect of Charge Distribution on the Dynamics of Polyampholytic Disordered Proteins.

Publications

Effect of Charge Distribution on the Dynamics of Polyampholytic Disordered Proteins.

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