scholarly journals Wavelet coherence phases decode the universal switching mechanism of Ras GTPase superfamily

2020 ◽  
Author(s):  
Zenia Motiwala ◽  
Anand S Sandholu ◽  
Durba Sengupta ◽  
Kiran Kulkarni
Keyword(s):  
Conformational Changes ◽  
Structural Changes ◽  
Statistical Significance ◽  
Md Simulations ◽  
Wavelet Coherence ◽  
Switching Mechanism ◽  
Novel Approach ◽  
Ras Superfamily ◽  
Functional States ◽  
Wavelet Coherence Analysis

Ras superfamily GTPases are molecular switches which regulate critical cellular processes. Extensive structural and computational studies on these G proteins have established a general framework for their switching mechanism, which involves conformational changes in their two loops, Switch I and Switch II, upon GTP binding and hydrolysis. Since the extent of these conformational changes is not uniform amongst the members of the Ras superfamily, there is no generic modus operandi defining their switching mechanism. Here, we have developed a novel approach employing wavelet coherence analysis to correlate the structural changes with their functional states. Our analysis shows that the structural coupling between the Switch I and Switch II regions is manifested in terms of conserved wavelet coherence phases, which could serve as useful parameters to define functional states of the GTPases. In oncogenic GTPases mutants, this phase coupling gets disentangled, which perhaps provides an alternative explanation for their aberrant function. We have tested the statistical significance of the observed phase angle correlations on multiple switch region conformers, generated through MD simulations.

scholarly journals Assessment of the PETase Conformational Changes Induced by Poly(ethylene terephthalate) Binding

2021 ◽  
Author(s):  
Clauber Henrique Costa ◽  
Alberto dos Santos ◽  
Cláudio Nahum Alves ◽  
Sérgio Martí ◽  
Vicente Moliner ◽  
...  
Keyword(s):  
Thermal Stability ◽  
Conformational Changes ◽  
Active Site ◽  
Terephthalic Acid ◽  
Structural Changes ◽  
Ethylene Terephthalate ◽  
Md Simulations ◽  
Poly Ethylene Terephthalate ◽  
Bounded State ◽  
Poly Ethylene

Recently, a bacterium strain of Ideonella sakaiensis was identified with the uncommon ability to degrade the poly(ethylene terephthalate) (PET). The PETase from I. sakaiensis strain 201-F6 catalyzes the hydrolysis of PET converting it to mono(2-hydroxyethyl) terephthalic acid (MHET), bis(2-hydroxyethyl)-TPA (BHET), and terephthalic acid (TPA). Despite the potential of this enzyme for mitigation or elimination of environmental contaminants, one of the limitations of the use of PETase for PET degradation is the fact that it acts only at moderate temperature due to its low thermal stability. Besides, molecular details of the main interaction of PET in the active site of PETase remains unclear. Herein, molecular docking and molecular dynamics (MD) simulations were applied to analyze structural changes of PETase induced by PET binding. Results from the essential dynamics revealed that β1-β2 connecting loop is very flexible. This Loop is located far from the active site of PETase and we suggest that it can be considered for mutagenesis in order to increase the thermal stability of PETase. The free energy landscape (FEL) demonstrates that the main change in the transition between the unbounded to the bounded state is associated with β7-α5 connecting loop, where the catalytic residue Asp206 is located. Overall, the present study provides insights into the molecular binding mechanism of PET into the PETase structure and a computational strategy for mapping flexible regions of this enzyme, which can be useful for the engineering of more efficient enzymes for recycling the plastic polymers using biological systems.

Protein-induced conformational changes in 16S rRNA during assembly of the Escherichia Coli 30S ribosomal subunit: A STEM study

1987 ◽  
Vol 45 ◽  
pp. 910-911
Author(s):  
M. Boublik ◽  
V. Mandiyan ◽  
J.F. Hainfeld ◽  
J.S. Wall
Keyword(s):  
16S Rrna ◽  
Conformational Changes ◽  
Ribosomal Proteins ◽  
Structural Changes ◽  
Ribosomal Subunit ◽  
Compact Structure ◽  
E Coli ◽  
Freeze Dried ◽  
16S Rna ◽  
30S Subunit

The aim of this study is to understand the mechanism of 16S rRNA folding into the compact structure of the small 30S subunit of E. coli ribosome. The assembly of the 30S E. coli ribosomal subunit is a sequence of specific interactions of 16S rRNA with 21 ribosomal proteins (S1-S21). Using dedicated high resolution STEM we have monitored structural changes induced in 16S rRNA by the proteins S4, S8, S15 and S20 which are involved in the initial steps of 30S subunit assembly. S4 is the first protein to bind directly and stoichiometrically to 16S rRNA. Direct binding also occurs individually between 16S RNA and S8 and S15. However, binding of S20 requires the presence of S4 and S8. The RNA-protein complexes are prepared by the standard reconstitution procedure, dialyzed against 60 mM KCl, 2 mM Mg(OAc)2, 10 mM-Hepes-KOH pH 7.5 (Buffer A), freeze-dried and observed unstained in dark field at -160°.

Influence of Ascorbic Acid on the Structure and Function of Alpha-2- macroglobulin: Investigations using Spectroscopic and Thermodynamic Techniques

2020 ◽  
Vol 27 (3) ◽  
pp. 201-209
Author(s):  
Syed Saqib Ali ◽  
Mohammad Khalid Zia ◽  
Tooba Siddiqui ◽  
Haseeb Ahsan ◽  
Fahim Halim Khan
Keyword(s):  
Ascorbic Acid ◽  
Conformational Changes ◽  
Structural Changes ◽  
The Body ◽  
Titration Calorimetry ◽  
Spectroscopic Techniques ◽  
Human Beings ◽  
Plasma Ascorbic Acid ◽  
Dietary Antioxidant ◽  
And Function

Background: Ascorbic acid is a classic dietary antioxidant which plays an important role in the body of human beings. It is commonly found in various foods as well as taken as dietary supplement. Objective: The plasma ascorbic acid concentration may range from low, as in chronic or acute oxidative stress to high if delivered intravenously during cancer treatment. Sheep alpha-2- macroglobulin (α2M), a human α2M homologue is a large tetrameric glycoprotein of 630 kDa with antiproteinase activity, found in sheep’s blood. Methods: In the present study, the interaction of ascorbic acid with alpha-2-macroglobulin was explored in the presence of visible light by utilizing various spectroscopic techniques and isothermal titration calorimetry (ITC). Results: UV-vis and fluorescence spectroscopy suggests the formation of a complex between ascorbic acid and α2M apparent by increased absorbance and decreased fluorescence. Secondary structural changes in the α2M were investigated by CD and FT-IR spectroscopy. Our findings suggest the induction of subtle conformational changes in α2M induced by ascorbic acid. Thermodynamics signatures of ascorbic acid and α2M interaction indicate that the binding is an enthalpy-driven process. Conclusion: It is possible that ascorbic acid binds and compromises antiproteinase activity of α2M by inducing changes in the secondary structure of the protein.

Closing the gap: an atomistic structural and functional perspective of S. mansoni universal stress G4LZI3 protein in complex with phenolic compounds

2020 ◽  
Vol 17 ◽  
Author(s):  
Priscilla Masamba ◽  
Geraldene Munsamy ◽  
Abidemi Paul Kappo
Keyword(s):  
Phenolic Compounds ◽  
Conformational Changes ◽  
Stress Protein ◽  
Md Simulations ◽  
Binding Energies ◽  
Developmental Cycle ◽  
Structure Based Drug Design ◽  
Bioinformatic Tools ◽  
Drug Of Choice ◽  
Functional Perspective

Background: For decades, Praziquantel has been the undisputed drug of choice for all schistosome infections, but rising concerns due to the unelucidated mechanism of action of the drug and unavoidable reports of emerging drug resistant strains has necessitated the need for alternative treatment drug. Moreover, current apprehension has been reinforced by total dependence on the drug for treatment hence, the search for novel and effective anti-schistosomal drugs. Uses: This study made use of bioinformatic tools to determine the structural binding of the Universal G4LZI3 stress protein (USP) in complex with ten polyphenol compounds, thereby highlighting the effectiveness of these recently identified ‘lead’ molecules in the design of novel therapeutics targeted against schistosomiasis. Upregulation of the G4LZI3 USP throughout the schistosome multifaceted developmental cycle sparks interest in its potential role as a druggable target. The integration of in silico tools provides an atomistic perspective into the binding of potential inhibitors to target proteins. Conclusion: This study therefore, implemented the use of molecular dynamic (MD) simulations to provide functional and structural insight into key conformational changes upon binding of G4ZLI3 to these key phenolic compounds. Post-MD analyses revealed unique structural and conformational changes in the G4LZI3 protein in complex with curcumin and catechin respectively. These systems exhibited the highest binding energies, while the major interacting residues conserved in all the complexes provides a route map for structure-based drug design of novel compounds with enhanced inhibitory potency against the G4LZI3 protein. This study suggests an alternative approach for the development of anti-schistosomal drugs using natural compounds.

scholarly journals Correlation of membrane protein conformational and functional dynamics

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Raghavendar Reddy Sanganna Gari ◽  
Joel José Montalvo‐Acosta ◽  
George R. Heath ◽  
Yining Jiang ◽  
Xiaolong Gao ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Conformational Changes ◽  
Single Channel ◽  
Conformational Dynamics ◽  
Md Simulations ◽  
High Temporal Resolution ◽  
Dependent Manner ◽  
Functional Dynamics ◽  
Ph Dependent ◽  
Open States

AbstractConformational changes in ion channels lead to gating of an ion-conductive pore. Ion flux has been measured with high temporal resolution by single-channel electrophysiology for decades. However, correlation between functional and conformational dynamics remained difficult, lacking experimental techniques to monitor sub-millisecond conformational changes. Here, we use the outer membrane protein G (OmpG) as a model system where loop-6 opens and closes the β-barrel pore like a lid in a pH-dependent manner. Functionally, single-channel electrophysiology shows that while closed states are favored at acidic pH and open states are favored at physiological pH, both states coexist and rapidly interchange in all conditions. Using HS-AFM height spectroscopy (HS-AFM-HS), we monitor sub-millisecond loop-6 conformational dynamics, and compare them to the functional dynamics from single-channel recordings, while MD simulations provide atomistic details and energy landscapes of the pH-dependent loop-6 fluctuations. HS-AFM-HS offers new opportunities to analyze conformational dynamics at timescales of domain and loop fluctuations.

scholarly journals Ligand-induced structural changes analysis of ribose-binding protein as studied by molecular dynamics simulations

2021 ◽  
pp. 1-12
Author(s):  
Haiyan Li ◽  
Zanxia Cao ◽  
Guodong Hu ◽  
Liling Zhao ◽  
Chunling Wang ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Structural Changes ◽  
Binding Protein ◽  
Network Models ◽  
Md Simulations ◽  
Protein Domain ◽  
Opening Angle ◽  
Conformation Changes ◽  
Wide Range ◽  
Ribose Binding Protein

BACKGROUND: The ribose-binding protein (RBP) from Escherichia coli is one of the representative structures of periplasmic binding proteins. Binding of ribose at the cleft between two domains causes a conformational change corresponding to a closure of two domains around the ligand. The RBP has been crystallized in the open and closed conformations. OBJECTIVE: With the complex trajectory as a control, our goal was to study the conformation changes induced by the detachment of the ligand, and the results have been revealed from two computational tools, MD simulations and elastic network models. METHODS: Molecular dynamics (MD) simulations were performed to study the conformation changes of RBP starting from the open-apo, closed-holo and closed-apo conformations. RESULTS: The evolution of the domain opening angle θ clearly indicates large structural changes. The simulations indicate that the closed states in the absence of ribose are inclined to transition to the open states and that ribose-free RBP exists in a wide range of conformations. The first three dominant principal motions derived from the closed-apo trajectories, consisting of rotating, bending and twisting motions, account for the major rearrangement of the domains from the closed to the open conformation. CONCLUSIONS: The motions showed a strong one-to-one correspondence with the slowest modes from our previous study of RBP with the anisotropic network model (ANM). The results obtained for RBP contribute to the generalization of robustness for protein domain motion studies using either the ANM or PCA for trajectories obtained from MD.

scholarly journals Thalamocortical Connectivity in Experimentally-Induced Migraine Attacks: A Pilot Study

2021 ◽  
Vol 11 (2) ◽  
pp. 165
Author(s):  
Daniele Martinelli ◽  
Gloria Castellazzi ◽  
Roberto De Icco ◽  
Ana Bacila ◽  
Marta Allena ◽  
...  
Keyword(s):  
Disease Model ◽  
Episodic Migraine ◽  
Wavelet Coherence ◽  
Test Time ◽  
Prodromal Phase ◽  
Brain Changes ◽  
The Right ◽  
Wavelet Coherence Analysis ◽  
Thalamic Function ◽  
Experimentally Induced

In this study we used nitroglycerin (NTG)-induced migraine attacks as a translational human disease model. Static and dynamic functional connectivity (FC) analyses were applied to study the associated functional brain changes. A spontaneous migraine-like attack was induced in five episodic migraine (EM) patients using a NTG challenge. Four task-free functional magnetic resonance imaging (fMRI) scans were acquired over the study: baseline, prodromal, full-blown, and recovery. Seed-based correlation analysis (SCA) was applied to fMRI data to assess static FC changes between the thalamus and the rest of the brain. Wavelet coherence analysis (WCA) was applied to test time-varying phase-coherence changes between the thalamus and salience networks (SNs). SCA results showed significantly FC changes between the right thalamus and areas involved in the pain circuits (insula, pons, cerebellum) during the prodromal phase, reaching its maximal alteration during the full-blown phase. WCA showed instead a loss of synchronisation between thalami and SN, mainly occurring during the prodrome and full-blown phases. These findings further support the idea that a temporal change in thalamic function occurs over the experimentally induced phases of NTG-induced headache in migraine patients. Correlation of FC changes with true clinical phases in spontaneous migraine would validate the utility of this model.

Metastability in Monolayer Films Transferred onto Solid Substrates by the Langmuir-Blodgett Method: IR Evidence for Transfer-Induced Phase Transitions

1994 ◽  
Vol 48 (10) ◽  
pp. 1196-1203 ◽  
Author(s):  
Fazale R. Rana ◽  
Suci Widayati ◽  
Brian W. Gregory ◽  
Richard A. Dluhy
Keyword(s):  
Fatty Acid ◽  
Conformational Changes ◽  
Structural Changes ◽  
High Surface ◽  
Solid Substrate ◽  
Water Interface ◽  
Monolayer Films ◽  
Langmuir Blodgett ◽  
Monomolecular Film ◽  
Air Water Interface

The rate at which a monomolecular film is deposited onto a solid substrate in the Langmuir-Blodgett process of preparing supported monolayer films influences the final structure of the transferred film. Attenuated total reflectance infrared spectroscopic studies of monolayers transferred to germanium substrates show that the speed at which the substrate is drawn through the air/water interface influences the final conformation in the hydrocarbon chains of amphiphilic film molecules. This transfer-induced effect is especially evident when the monolayer is transferred from the expanded region of surface-pressure-molecular-area isotherms at low surface pressures; the effect is minimized when the film molecules are transferred from condensed phases at high surface pressures. This phenomenon has been observed for both a fatty acid and a phospholipid, which suggests that these conformational changes may occur in a variety of hydrocarbon amphiphiles transferred from the air/water interface. This conformational ordering may be due to a kinetically limited phase transition taking place in the meniscus formed between the solid substrate and aqueous subphase. In addition, the results obtained for both the phospholipid and fatty acid suggest that the structure of the amphiphile may help determine the extent and nature of the transfer-speed-induced structural changes taking place in the monomolecular film.

New insights into the structural basis of integrin activation

Blood ◽  
2003 ◽  
Vol 102 (4) ◽  
pp. 1155-1159 ◽  
Author(s):  
Jian-Ping Xiong ◽  
Thilo Stehle ◽  
Simon L. Goodman ◽  
M. Amin Arnaout
Keyword(s):  
Conformational Changes ◽  
Structural Changes ◽  
Structural Basis ◽  
Integrin Activation ◽  
Cellular Functions ◽  
Electron Microscopic ◽  
The Past ◽  
Intracellular Signals ◽  
Bidirectional Signaling ◽  
New Hypothesis

Abstract Integrins are cell adhesion receptors that communicate biochemical and mechanical signals in a bidirectional manner across the plasma membrane and thus influence most cellular functions. Intracellular signals switch integrins into a ligand-competent state as a result of elicited conformational changes in the integrin ectodomain. Binding of extracellular ligands induces, in turn, structural changes that convey distinct signals to the cell interior. The structural basis of this bidirectional signaling has been the focus of intensive study for the past 3 decades. In this perspective, we develop a new hypothesis for integrin activation based on recent crystallographic, electron microscopic, and biochemical studies.

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