Capturing the Conformational Ensemble of the Mixed Folded Polyglutamine Protein Ataxin-3

Structure ◽  
2021 ◽  
Vol 29 (1) ◽  
pp. 70-81.e5
Author(s):  
Alessandro Sicorello ◽  
Bartosz Różycki ◽  
Petr V. Konarev ◽  
Dmitri I. Svergun ◽  
Annalisa Pastore
Keyword(s):  
Conformational Ensemble ◽  
Polyglutamine Protein

scholarly journals The structural plasticity of nucleic acid duplexes revealed by WAXS and MD

2021 ◽  
Vol 7 (17) ◽  
pp. eabf6106
Author(s):  
Weiwei He ◽  
Yen-Lin Chen ◽  
Lois Pollack ◽  
Serdal Kirmizialtin
Keyword(s):  
Structural Diversity ◽  
Conformational Ensemble ◽  
Structural Variations ◽  
Dna And Rna ◽  
X Ray Scattering ◽  
Double Stranded Dna ◽  
Binding Partners ◽  
Rna Duplexes ◽  
Dynamics Simulations ◽  
Integrate Solution

Double-stranded DNA (dsDNA) and RNA (dsRNA) helices display an unusual structural diversity. Some structural variations are linked to sequence and may serve as signaling units for protein-binding partners. Therefore, elucidating the mechanisms and factors that modulate these variations is of fundamental importance. While the structural diversity of dsDNA has been extensively studied, similar studies have not been performed for dsRNA. Because of the increasing awareness of RNA’s diverse biological roles, such studies are timely and increasingly important. We integrate solution x-ray scattering at wide angles (WAXS) with all-atom molecular dynamics simulations to explore the conformational ensemble of duplex topologies for different sequences and salt conditions. These tightly coordinated studies identify robust correlations between features in the WAXS profiles and duplex geometry and enable atomic-level insights into the structural diversity of DNA and RNA duplexes. Notably, dsRNA displays a marked sensitivity to the valence and identity of its associated cations.

scholarly journals Basic Residue Clusters in Intrinsically Disordered Regions of Peripheral Membrane Proteins: Modulating 2D Diffusion on Cell Membranes

Physchem ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 152-162
Author(s):  
Miquel Pons
Keyword(s):  
Membrane Proteins ◽  
Electrostatic Interactions ◽  
Lipid Membrane ◽  
Conformational Ensemble ◽  
Basic Residue ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Peripheral Membrane Proteins ◽  
Charged Residues ◽  
Disordered Regions

A large number of peripheral membrane proteins transiently interact with lipids through a combination of weak interactions. Among them, electrostatic interactions of clusters of positively charged amino acid residues with negatively charged lipids play an important role. Clusters of charged residues are often found in intrinsically disordered protein regions, which are highly abundant in the vicinity of the membrane forming what has been called the disordered boundary of the cell. Beyond contributing to the stability of the lipid-bound state, the pattern of charged residues may encode specific interactions or properties that form the basis of cell signaling. The element of this code may include, among others, the recognition, clustering, and selective release of phosphatidyl inositides, lipid-mediated protein-protein interactions changing the residence time of the peripheral membrane proteins or driving their approximation to integral membrane proteins. Boundary effects include reduction of dimensionality, protein reorientation, biassing of the conformational ensemble of disordered regions or enhanced 2D diffusion in the peri-membrane region enabled by the fuzzy character of the electrostatic interactions with an extended lipid membrane.

scholarly journals On the use of 3J-coupling NMR data to derive structural information on proteins

2021 ◽  
Vol 75 (1) ◽  
pp. 39-70
Author(s):  
Lorna J. Smith ◽  
Wilfred F. van Gunsteren ◽  
Bartosz Stankiewicz ◽  
Niels Hansen
Keyword(s):  
Protein Structure ◽  
Structural Information ◽  
Protein Structure Determination ◽  
High Sensitivity ◽  
Time Averaging ◽  
Conformational Ensemble ◽  
Torsional Angle ◽  
Conformational Variability ◽  
Egg White Lysozyme ◽  
Coupling Time

AbstractValues of 3J-couplings as obtained from NMR experiments on proteins cannot easily be used to determine protein structure due to the difficulty of accounting for the high sensitivity of intermediate 3J-coupling values (4–8 Hz) to the averaging period that must cover the conformational variability of the torsional angle related to the 3J-coupling, and due to the difficulty of handling the multiple-valued character of the inverse Karplus relation between torsional angle and 3J-coupling. Both problems can be solved by using 3J-coupling time-averaging local-elevation restraining MD simulation. Application to the protein hen egg white lysozyme using 213 backbone and side-chain 3J-coupling restraints shows that a conformational ensemble compatible with the experimental data can be obtained using this technique, and that accounting for averaging and the ability of the algorithm to escape from local minima for the torsional angle induced by the Karplus relation, are essential for a comprehensive use of 3J-coupling data in protein structure determination.

scholarly journals Heat shock factor 2 is required for maintaining proteostasis against febrile-range thermal stress and polyglutamine aggregation

2011 ◽  
Vol 22 (19) ◽  
pp. 3571-3583 ◽  
Author(s):  
Toyohide Shinkawa ◽  
Ke Tan ◽  
Mitsuaki Fujimoto ◽  
Naoki Hayashida ◽  
Kaoru Yamamoto ◽  
...  
Keyword(s):  
Thermal Stress ◽  
Heat Shock ◽  
Protein Misfolding ◽  
Reproductive Organs ◽  
Heat Shock Factors ◽  
Mild Heat ◽  
Promising Therapeutic Target ◽  
Αb Crystallin ◽  
Shock Proteins ◽  
Polyglutamine Protein

Heat shock response is characterized by the induction of heat shock proteins (HSPs), which facilitate protein folding, and non-HSP proteins with diverse functions, including protein degradation, and is regulated by heat shock factors (HSFs). HSF1 is a master regulator of HSP expression during heat shock in mammals, as is HSF3 in avians. HSF2 plays roles in development of the brain and reproductive organs. However, the fundamental roles of HSF2 in vertebrate cells have not been identified. Here we find that vertebrate HSF2 is activated during heat shock in the physiological range. HSF2 deficiency reduces threshold for chicken HSF3 or mouse HSF1 activation, resulting in increased HSP expression during mild heat shock. HSF2-null cells are more sensitive to sustained mild heat shock than wild-type cells, associated with the accumulation of ubiquitylated misfolded proteins. Furthermore, loss of HSF2 function increases the accumulation of aggregated polyglutamine protein and shortens the lifespan of R6/2 Huntington's disease mice, partly through αB-crystallin expression. These results identify HSF2 as a major regulator of proteostasis capacity against febrile-range thermal stress and suggest that HSF2 could be a promising therapeutic target for protein-misfolding diseases.

The Native State Conformational Ensemble of the SH3 Domain from α-Spectrin†

Biochemistry ◽  
1999 ◽  
Vol 38 (28) ◽  
pp. 8899-8906 ◽  
Author(s):  
Mourad Sadqi ◽  
Salvador Casares ◽  
María A. Abril ◽  
Obdulio López-Mayorga ◽  
Francisco Conejero-Lara ◽  
...  
Keyword(s):  
Sh3 Domain ◽  
Conformational Ensemble ◽  
Native State

scholarly journals Conformational ensemble of the sodium-coupled aspartate transporter

2013 ◽  
Vol 20 (2) ◽  
pp. 215-221 ◽  
Author(s):  
Elka R Georgieva ◽  
Peter P Borbat ◽  
Christopher Ginter ◽  
Jack H Freed ◽  
Olga Boudker
Keyword(s):  
Conformational Ensemble

scholarly journals Reinforcement Learning to Boost Molecular Docking upon Protein Conformational Ensemble

2021 ◽  
Author(s):  
Bin Chong ◽  
Yingguang Yang ◽  
Zi-Le Wang ◽  
Han Xing ◽  
Zhirong Liu
Keyword(s):  
Molecular Docking ◽  
Reinforcement Learning ◽  
Intrinsically Disordered Proteins ◽  
Therapeutic Targets ◽  
Human Diseases ◽  
Disordered Proteins ◽  
Conformational Ensemble ◽  
Intrinsically Disordered

Intrinsically disordered proteins (IDPs) widely involve in human diseases and are thus attractive therapeutic targets. In practice, however, it is computationally prohibitive to dock large ligand libraries to thousands and...

4D-QSAR models applied to the study of TGF- β1 receptor inhibitors

2021 ◽  
Vol 21 ◽  
Author(s):  
Tamiris Maria de Assis ◽  
Teodorico Castro Ramalho ◽  
Elaine Fontes Ferreira da Cunha
Keyword(s):  
External Validation ◽  
Qsar Model ◽  
Dynamics Simulation ◽  
Conformational Ensemble ◽  
Pyrimidine Derivatives ◽  
Statistical Parameters ◽  
Data Set ◽  
Mesenchymal Transition ◽  
Qsar Models ◽  
Tgf Β1

Background: The quantitative structure-activity relationship is an analysis method that can be applied for designing new molecules. In 1997, Hopfinger and coworkers developed the 4D-QSAR methodology aiming to eliminate the question of which conformation to use in a QSAR study. In this work, the 4D-QSAR methodology was used to quantitatively determine the influence of structural descriptors on the activity of aryl pyrimidine derivatives as inhibitors of the TGF-β1 receptor. The members of the TGF-β subfamily are interesting molecular targets, since they play an important function in the growth and development of cell cellular including proliferation, apoptosis, differentiation, epithelial-mesenchymal transition (EMT), and migration. In late stages, TGF-β exerts tumor-promoting effects, increasing tumor invasiveness, and metastasis. Therefore, TGF-β is an attractive target for cancer therapy. Objective: The major goal of the current research is to develop 4D-QSAR models aiming to propose new structures of aryl pyrimidine derivatives. Materials and Methods: Molecular dynamics simulation was carried out to generate the conformational ensemble profile of a data set with aryl pyrimidine derivatives. The conformations were overlaid into a three-dimensional cubic box, according to the three-ordered atom alignment. The occupation of the grid cells by the interaction of pharmacophore elements provides the grid cell occupancy descriptors (GCOD), the dependent variables used to build the 4D-QSAR models. The best models were validated (internal and external validation) using several statistical parameters. Docking molecular studies were performed to better understand the binding mode of pyrimidine derivatives inside the TGF-β active site. Results : The 4D-QSAR model presented seven descriptors and acceptable statistical parameters (R2 = 0.89, q2 = 0.68, R2pred = 0.65, r2m = 0.55, R2P = 0.68 and R2rand = 0.21) besides pharmacophores groups important for the activity of these compounds. The molecular docking studies helped to understand the pharmacophoric groups and proposed substituents that increase the potency of aryl pyrimidine derivatives. Conclusion: The best QSAR model showed adequate statistical parameters that ensure their fitness, robustness, and predictivity. Structural modifications were assessed, and five new structures were proposed as candidates for a drug for cancer treatment.

Sign in / Sign up

Export Citation Format

Share Document