Effects of flexibility and electrostatic interactions on the coupled binding–folding mechanisms of Chz.core and H2A.z–H2B

2017 ◽  
Vol 13 (10) ◽  
pp. 2152-2159 ◽  
Author(s):  
Xu Shang ◽  
Wenting Chu ◽  
Xiakun Chu ◽  
Chuanbo Liu ◽  
Liufang Xu ◽  
...  
Keyword(s):  
Free Energy ◽  
Electrostatic Interactions ◽  
Intrinsically Disordered Protein ◽  
Histone Variant ◽  
Energy Landscapes ◽  
Binding Mechanism ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Binding Preference ◽  
Free Energy Landscapes

The intrinsically disordered protein (IDP) Chz.core, which is the interaction core of Chz1, shows binding preference to histone variant H2A.z. The coupled folding–binding mechanism of the complex can be quantified by the free energy landscapes.

The regulation mechanism of phosphorylation and mutations in intrinsically disordered protein 4E-BP2

2020 ◽  
Vol 22 (5) ◽  
pp. 2938-2948
Author(s):  
Ke Wang ◽  
Shangbo Ning ◽  
Yue Guo ◽  
Mojie Duan ◽  
Minghui Yang
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Intrinsically Disordered Protein ◽  
Regulation Mechanism ◽  
Energy Landscapes ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Free Energy Landscapes

The free energy landscapes of 4E-BP2 and its variants were obtained by replica-exchanged molecular dynamics, which elucidate the regulation mechanism of phosphorylation and mutations on the intrinsically disordered protein.

scholarly journals Mediator subunit Med15 dictates the conserved “fuzzy” binding mechanism of yeast transcription activators Gal4 and Gcn4

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lisa M. Tuttle ◽  
Derek Pacheco ◽  
Linda Warfield ◽  
Damien B. Wilburn ◽  
Steven Hahn ◽  
...  
Keyword(s):  
Intrinsically Disordered Protein ◽  
Activation Function ◽  
Binding Mechanism ◽  
Binding Partner ◽  
Protein Protein Interaction ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Independent Mechanism ◽  
Transcription Activators ◽  
Common Sequence

AbstractThe acidic activation domain (AD) of yeast transcription factor Gal4 plays a dual role in transcription repression and activation through binding to Gal80 repressor and Mediator subunit Med15. The activation function of Gal4 arises from two hydrophobic regions within the 40-residue AD. We show by NMR that each AD region binds the Mediator subunit Med15 using a “fuzzy” protein interface. Remarkably, comparison of chemical shift perturbations shows that Gal4 and Gcn4, two intrinsically disordered ADs of different sequence, interact nearly identically with Med15. The finding that two ADs of different sequence use an identical fuzzy binding mechanism shows a common sequence-independent mechanism for AD-Mediator binding, similar to interactions within a hydrophobic cloud. In contrast, the same region of Gal4 AD interacts strongly with Gal80 via a distinct structured complex, implying that the structured binding partner of an intrinsically disordered protein dictates the type of protein–protein interaction.

scholarly journals Anomalous Salt Dependence Reveals an Interplay of Attractive and Repulsive Electrostatic Interactions in α-synuclein Fibril Formation

QRB Discovery ◽  
2020 ◽  
Vol 1 ◽  
Author(s):  
Ricardo Gaspar ◽  
Mikael Lund ◽  
Emma Sparr ◽  
Sara Linse
Keyword(s):  
Ionic Strength ◽  
Electrostatic Interactions ◽  
Intrinsically Disordered Protein ◽  
Lipid Vesicles ◽  
Intrinsically Disordered ◽  
Catalytic Surfaces ◽  
Disordered Protein ◽  
Salt Dependence ◽  
Fluorescence Measurements ◽  
The One

Abstractα-Synuclein (α-syn) is an intrinsically disordered protein with a highly asymmetric charge distribution, whose aggregation is linked to Parkinson’s disease. The effect of ionic strength was investigated at mildly acidic pH (5.5) in the presence of catalytic surfaces in the form of α-syn seeds or anionic lipid vesicles using thioflavin T fluorescence measurements. Similar trends were observed with both surfaces: increasing ionic strength reduced the rate of α-syn aggregation although the surfaces as well as α-syn have a net negative charge at pH 5.5. This anomalous salt dependence implies that short-range attractive electrostatic interactions are critical for secondary nucleation as well as heterogeneous primary nucleation. Such interactions were confirmed in Monte Carlo simulations of α-syn monomers interacting with surface-grafted C-terminal tails, and found to be weakened in the presence of salt. Thus, nucleation of α-syn aggregation depends critically on an attractive electrostatic component that is screened by salt to the extent that it outweighs the screening of the long-range repulsion between negatively charged monomers and negative surfaces. Interactions between the positively charged N-termini of α-syn monomers on the one hand, and the negatively C-termini of α-syn on fibrils or vesicles surfaces on the other hand, are thus critical for nucleation.

scholarly journals High resolution ensemble description of metamorphic and intrinsically disordered proteins using an efficient hybrid parallel tempering scheme

2020 ◽  
Author(s):  
Rajeswari Appadurai ◽  
Jayashree Nagesh ◽  
Anand Srivastava
Keyword(s):  
Free Energy ◽  
Sampling Method ◽  
Intrinsically Disordered Proteins ◽  
Md Simulations ◽  
Disordered Proteins ◽  
Parallel Tempering ◽  
Energy Landscapes ◽  
Intrinsically Disordered ◽  
Advanced Sampling ◽  
Free Energy Landscapes

AbstractDetermining the conformational ensemble for proteins with multi-funneled complex free-energy landscapes is often not possible with classical structure-biology methods that produce time and ensemble averaged data. With vastly improved force fields and advances in rare-event sampling methods, molecular dynamics (MD) simulations offer a complementary approach towards determining the collection of 3-dimensional structures that proteins can adopt. However, in general, MD simulations need to either impose restraints or reweigh the generated data to match experiments. The limitations extend beyond systems with high free-energy barriers as is the case with metamorphic proteins such as RFA-H. The predicted structures in even weakly-funneled intrinsically disordered proteins (IDPs) such as Histatin-5 (His-5) are too compact relative to experiments. Here, we employ a new computationally-efficient parallel-tempering based advanced-sampling method applicable across proteins with extremely diverse free-energy landscapes. And we show that the calculated ensemble averages match reasonably well with the NMR, SAXS and other biophysical experiments without the need to reweigh. We benchmark our method against standard model systems such as alanine di-peptide, TRP-cage and β-hairpin and demonstrate significant enhancement in the sampling efficiency. The method successfully scales to large metamorphic proteins such as RFA-H and to highly disordered IDPs such as His-5 and produces experimentally-consistent ensemble. By allowing accurate sampling across diverse landscapes, the method enables for ensemble conformational sampling of deep multi-funneled metamorphic proteins as well as highly flexible IDPs with shallow multi-funneled free-energy landscape.Significance/Authors’ SummaryGenerating high-resolution ensemble of intrinsically disordered proteins, particularly the highly flexible ones with high-charge and low-hydrophobicity and with shallow multi-funneled free-energy landscape, is a daunting task and often not possible since information from biophysical experiments provide time and ensemble average data at low resolutions. At the other end of the spectrum are the metamorphic proteins with multiple deep funnels and elucidating the structures of the transition intermediates between the fold topologies is a non-trivial exercise. In this work, we propose a new parallel-tempering based advanced-sampling method where the Hamiltonian is designed to allow faster decay of water orientation dynamics, which in turn facilitates accurate and efficient sampling across a wide variety of free-energy landscapes.

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