Fluorescence Depolarization Kinetics Captures Short-Range Backbone Dihedral Rotations and Long-Range Correlated Dynamics of an Intrinsically Disordered Protein

Das, Debapriya; Arora, Lisha; Mukhopadhyay, Samrat

doi:10.1021/acs.jpcb.1c04426

Cited by 7 publications

(37 citation statements)

References 62 publications

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“…A similar hierarchy of time scales has been observed by fluorescence depolarization kinetics measurements of α-synuclein. [ 48 ] These collective motions involve medium to longer-range interactions between residues that can be elucidated by graph theoretical analysis of the MD trajectories described here. For Pup, many of these slower motional modes have correlation times around 3–4 ns whereas for p53TAD they are on average twice as large.…”

Section: Discussionmentioning

confidence: 99%

“…Such information is important for understanding recognition events between IDPs and their binding targets, including IDP interactions with other disordered biomolecules, for example, during the formation of LLPS condensates. Experimental IDP dynamics information can be gained from fluorescence depolarization spectroscopy, [48] Fo ¨rster resonance energy transfer (FRET), [16] and nuclear magnetic resonance (NMR) relaxation. [15] NMR 15 N longitudinal R 1 and transverse R 2 spin relaxation rates are exquisitely sensitive to the dynamics of disordered proteins and the underlying time scales.…”

Section: Introductionmentioning

confidence: 99%

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Quantitative prediction of ensemble dynamics, shapes and contact propensities of intrinsically disordered proteins

Brüschweiler

2022

PLoS Comput Biol

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Intrinsically disordered proteins (IDPs) are highly dynamic systems that play an important role in cell signaling processes and their misfunction often causes human disease. Proper understanding of IDP function not only requires the realistic characterization of their three-dimensional conformational ensembles at atomic-level resolution but also of the time scales of interconversion between their conformational substates. Large sets of experimental data are often used in combination with molecular modeling to restrain or bias models to improve agreement with experiment. It is shown here for the N-terminal transactivation domain of p53 (p53TAD) and Pup, which are two IDPs that fold upon binding to their targets, how the latest advancements in molecular dynamics (MD) simulations methodology produces native conformational ensembles by combining replica exchange with series of microsecond MD simulations. They closely reproduce experimental data at the global conformational ensemble level, in terms of the distribution properties of the radius of gyration tensor, and at the local level, in terms of NMR properties including 15N spin relaxation, without the need for reweighting. Further inspection revealed that 10–20% of the individual MD trajectories display the formation of secondary structures not observed in the experimental NMR data. The IDP ensembles were analyzed by graph theory to identify dominant inter-residue contact clusters and characteristic amino-acid contact propensities. These findings indicate that modern MD force fields with residue-specific backbone potentials can produce highly realistic IDP ensembles sampling a hierarchy of nano- and picosecond time scales providing new insights into their biological function.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Quantitative prediction of ensemble dynamics, shapes and contact propensities of intrinsically disordered proteins

Brüschweiler

2022

PLoS Comput Biol

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“…IDPs are exceptionally rich in polar and charged residues in comparison to globular proteins [3,4], which results in a plethora of structural states that are separated by low energy barriers [5]. These characteristics allow IDPs to dynamically sample a huge conformational ensemble by means of large-scale correlated motions of the protein chain [6,7] that are connected to backbone torsional rotations occurring on short length ranges [8,9]. Concurrently, IDPs are highly susceptible in their structural and dynamical response to external perturbations, e.g., variation of ionic strength [10] or solution osmolarity [11], and this constitutes an inherent mechanism of IDPs to respond to local variations of the intracellular medium [12].…”

Section: Introductionmentioning

confidence: 99%

Variation of Structural and Dynamical Flexibility of Myelin Basic Protein in Response to Guanidinium Chloride

Haris

Biehl

Dulle

et al. 2022

IJMS

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Myelin basic protein (MBP) is intrinsically disordered in solution and is considered as a conformationally flexible biomacromolecule. Here, we present a study on perturbation of MBP structure and dynamics by the denaturant guanidinium chloride (GndCl) using small-angle scattering and neutron spin–echo spectroscopy (NSE). A concentration of 0.2 M GndCl causes charge screening in MBP resulting in a compact, but still disordered protein conformation, while GndCl concentrations above 1 M lead to structural expansion and swelling of MBP. NSE data of MBP were analyzed using the Zimm model with internal friction (ZIF) and normal mode (NM) analysis. A significant contribution of internal friction was found in compact states of MBP that approaches a non-vanishing internal friction relaxation time of approximately 40 ns at high GndCl concentrations. NM analysis demonstrates that the relaxation rates of internal modes of MBP remain unaffected by GndCl, while structural expansion due to GndCl results in increased amplitudes of internal motions. Within the model of the Brownian oscillator our observations can be rationalized by a loss of friction within the protein due to structural expansion. Our study highlights the intimate coupling of structural and dynamical plasticity of MBP, and its fundamental difference to the behavior of ideal polymers in solution.

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“…Such information is important for understanding recognition events between IDPs and their binding targets, including IDP interactions with other disordered biomolecules, for example, during the formation of LLPS condensates. Experimental IDP dynamics information can be gained from fluorescence depolarization spectroscopy, (48) Förster resonance energy transfer (FRET), (16) and nuclear magnetic resonance (NMR) relaxation. (15) NMR 15 N longitudinal R1 and transverse R2 spin relaxation rates are exquisitely sensitive to the dynamics of disordered proteins and the underlying time scales.…”

Section: Introductionmentioning

confidence: 99%

Quantitative prediction of ensemble dynamics, shapes and contact propensities of intrinsically disordered proteins

Brüschweiler

2022

Preprint

View full text Add to dashboard Cite

Intrinsically disordered proteins (IDPs) are highly dynamic systems that play an important role in cell signaling processes and their misfunction often causes human disease. Proper understanding of IDP function not only requires the realistic characterization of their three-dimensional conformational ensembles at atomic-level resolution but also of the time scales of interconversion between their conformational substates. Large sets of experimental data are often used in combination with molecular modeling to restrain or bias models to improve agreement with experiment. It is shown here for the N-terminal transactivation domain of p53 (p53TAD) and Pup how the latest advancements in molecular dynamics (MD) simulations methodology produces native conformational ensembles by combining replica exchange with series of microsecond MD simulations. They closely reproduce experimental data at the global conformational ensemble level, in terms of the distribution properties of the radius of gyration tensor, and at the local level, in terms of NMR properties including 15N spin relaxation, without the need for reweighting. The IDP ensembles were analyzed by graph theory to identify dominant inter-residue contact clusters and characteristic amino-acid contact propensities. These findings indicate that modern MD force fields with residue-specific backbone potentials can produce highly realistic IDP ensembles sampling a hierarchy of nano- and picosecond time scales providing new insights into their biological function.

show abstract

Fluorescence Depolarization Kinetics Captures Short-Range Backbone Dihedral Rotations and Long-Range Correlated Dynamics of an Intrinsically Disordered Protein

Cited by 7 publications

References 62 publications

Quantitative prediction of ensemble dynamics, shapes and contact propensities of intrinsically disordered proteins

Quantitative prediction of ensemble dynamics, shapes and contact propensities of intrinsically disordered proteins

Variation of Structural and Dynamical Flexibility of Myelin Basic Protein in Response to Guanidinium Chloride

Quantitative prediction of ensemble dynamics, shapes and contact propensities of intrinsically disordered proteins

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