scholarly journals Does Covera-19 know ‘when to hold ‘em or ‘when to fold ‘em? A translational thought experiment

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Gerald Dieter Griffin
Keyword(s):  
Conformational Changes ◽  
Structural Changes ◽  
Structural Integrity ◽  
Thought Experiment ◽  
Amino Acid Sequences ◽  
Acid And Base ◽  
Effects Of Ph ◽  
Base Balance ◽  
Environmental Milieu ◽  
And Function

AbstractThe function of proteins depends on their structure. The structural integrity of proteins is dynamic and depends on interacting nearby neighboring moieties that influence their properties and induce folding and structural changes. The conformational changes induced by these nearby neighbors in the micro-environmental milieu at that moment are guided by chemical or electrical bonding attractions.There are few literature references that describe the potential for environmental milieu changes to disfavor SARS-CoV-2 attachment to a receptor for survival outside of a host. There are many studies on the effects of pH (acid and base balance) supporting its importance for protein structure and function, but few focus on pH role in extracellular or intracellular protein or actionable requirements of Covera-19.‘Fold ‘em or Hold ‘em’ is seen by the various functions and effects of furin as it seeks an acidic milieu for action or compatible amino acid sequences which is currently aided by its histidine component and the structural changes of proteins as they enter or exit the host. Questions throughout the text are posed to focus on current thoughts as reviewing applicable COVID-19 translational research science in order to understand the complexities of Covid-19.The pH needs of COVID-19 players and its journey through the human host and environment as well as some efficacious readily available repurposed drugs and out-of-the box and easily available treatments are reviewed.

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.

scholarly journals NCIPLOT4: A New Step Towards a Fast Quantification of Noncovalent Interactions

2019 ◽  
Author(s):  
Roberto Boto ◽  
Francesca Peccati ◽  
Rubén Laplaza ◽  
chaoyu quan ◽  
Alessandra Carbone ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Structural Changes ◽  
Driving Forces ◽  
Noncovalent Interactions ◽  
Noncovalent Interaction ◽  
Simple Approach ◽  
Machine Learning Algorithms ◽  
Definition Of ◽  
And Function ◽  
The Relationship

<br>The quantification of noncovalent interactions in big systems is of crucial importance for understanding the structure and function of biosystems. The NCI method [J. Am. Chem. Soc. 132 , 6498 (2010)] enables to identify attractive and repulsive noncovalent interactions from promolecular densities in a fast manner. However, the approach remained up to now visual/qualitative, the relationship with energetics was conspicuously missing. We present a new version of NCIPLOT which allows quantifying the properties of the NonCovalent Interaction (NCI) regions in a fast manner. In order to do so, the definition of NCI volumes is introduced, which allows quantification of intra and intermolecular NCI properties in big systems where wavefunctions are not available. The connection between these integrals and energetics is reviewed for benchmark systems (S66 8), showing that our simple approach can lead to GGAquality energies while scaling with the number of atoms involved in the interaction (not the total number of atoms). The new implementation also includes an adaptive grid which allows the computation in a fast, parallelizable and efficient computational environment. The relationship with energetics derived from force fields is highlighted<br>and the faster algorithm exploited to analyze the evolution of interactions along MD trajectories. Through machine learning algorithms we characterize the relevance of NCI integrals in understanding the energetics of big systems, which is then applied in revealing the energetic changes along conformational changes, as well as identifying the atoms involved. This simple approach enables to identify the driving forces in biomolecular structural changes both at the spatial and energetic levels, while going beyond a mere parametrized-distances analysis.<br>

NCIPLOT4: A New Step Towards a Fast Quantification of Noncovalent Interactions

2020 ◽  
Author(s):  
Roberto Boto ◽  
Francesca Peccati ◽  
Rubén Laplaza ◽  
chaoyu quan ◽  
Alessandra Carbone ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Structural Changes ◽  
Driving Forces ◽  
Noncovalent Interactions ◽  
Noncovalent Interaction ◽  
Simple Approach ◽  
Machine Learning Algorithms ◽  
Definition Of ◽  
And Function ◽  
The Relationship

<br>The quantification of noncovalent interactions in big systems is of crucial importance for understanding the structure and function of biosystems. The NCI method [J. Am. Chem. Soc. 132 , 6498 (2010)] enables to identify attractive and repulsive noncovalent interactions from promolecular densities in a fast manner. However, the approach remained up to now visual/qualitative, the relationship with energetics was conspicuously missing. We present a new version of NCIPLOT which allows quantifying the properties of the NonCovalent Interaction (NCI) regions in a fast manner. In order to do so, the definition of NCI volumes is introduced, which allows quantification of intra and intermolecular NCI properties in big systems where wavefunctions are not available. The connection between these integrals and energetics is reviewed for benchmark systems (S66 8), showing that our simple approach can lead to GGAquality energies while scaling with the number of atoms involved in the interaction (not the total number of atoms). The new implementation also includes an adaptive grid which allows the computation in a fast, parallelizable and efficient computational environment. The relationship with energetics derived from force fields is highlighted<br>and the faster algorithm exploited to analyze the evolution of interactions along MD trajectories. Through machine learning algorithms we characterize the relevance of NCI integrals in understanding the energetics of big systems, which is then applied in revealing the energetic changes along conformational changes, as well as identifying the atoms involved. This simple approach enables to identify the driving forces in biomolecular structural changes both at the spatial and energetic levels, while going beyond a mere parametrized-distances analysis.<br>

scholarly journals Molecular Dynamics of SARS-CoV-2 Nsp1 Structural Changes Associated with Variant Mutations

2021 ◽  
Author(s):  
Shokouh Rezaei ◽  
Yahya Sefidbakht ◽  
Filipe Pereira
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Structural Changes ◽  
Structure And Function ◽  
Dynamics Simulation ◽  
Structural Protein ◽  
Wild Type ◽  
Deletion Mutations ◽  
And Function

Abstract SARS-CoV-2 non-structural protein 1 (Nsp1) is a virulence factor that inhibits the translation of host mRNAs and interact with viral RNA. Despite the relevance of Nsp1, few studies have been conducted to understand the effect of mutations on Nsp1 structure and function. Here, we provide a molecular dynamics simulation of SARS-CoV-2 Nsp1, wild type and variants. We found that SARS-CoV-2 Nsp1 has a more Rg value than SARS-CoV-1 Nsp1, with indicate an effect on the folding protein. This result suggest that SARS-CoV-2 Nsp1 can more easily approach the active site of the ribosome compared to SARS-CoV-1 Nsp1. In addition, we found that the C-terminal of the SARS-CoV-2 Nsp1, in particular residues 164 to 170, are more flexible than other regions of SARS-CoV-2 Nsp1 and SARS-CoV-1 Nsp1, confirming the role of this region in the interaction with the 40S subunit. Moreover, multiple deletion mutations have been found in the N/C-terminal of the SARS-CoV-2 Nsp1, which seems the effect of SARS-CoV-2 Nsp1 multiple deletions is greater than that of substitutions. Among all deletions, D156-158 and D80-90 may destabilize the protein structure and possibly increase the virulence of the SARS-CoV-2. Overall, our findings reinforce the importance of studying Nsp1 conformational changes in new variants and its effect on virulence of SARS-CoV-2.

PEPTIDES FROM FIBRINOGENAND FIBRONECTIN CHANGE THE CONFORMATIONOF PURIFIED PLATELET GLYCOPROTEIN IIb-IIIa

1987 ◽  
Author(s):  
L V Parise ◽  
B Steiner ◽  
L Nannizzi ◽  
D A Phillips
Keyword(s):  
Conformational Changes ◽  
Amino Acid Sequences ◽  
Platelet Glycoprotein ◽  
Maximal Effect ◽  
Hydrodynamic Properties ◽  
Platelet Surface ◽  
Specific Amino Acid ◽  
Fibrinogen Binding ◽  
A Chain ◽  
And Function

Specific amino acid sequences in fibrinogen and fibronectin appear to mediate the binding of these ligands to the glycoprotein (GP) IIb-IIIacomplex in platelets. Thesesequences include LGGAKQAGDV from the y chain of fibrinogen, and RGD(S) from the a chain of fibrinogenand the cell-binding domain of fibronectin. Several recent reports suggest thatfibrinogen and/or peptides with these sequences cause clustering of GPIIb-IIIa on the platelet surface and Na+/H+ exchange in epinephrine-stimulated platelets. Thus, it is possible that occupancy of specific sites on GP Ilb-IIIa affects its conformation, initiating such events. In this study,we determined whether LGGAKQAGDV, RGDS, and related peptides affect the conformation of purified platelet GP IIb-IIIa. Conformational changes in GP IIb-IIIa were evaluated bychanges in proteolytic susceptibility and hydrodynamic properties. Thepurified GP IIb-IIIa complex was fund to be resistant to proteolysis bythrombin. However, pretreatment of GP IIb-IIIa with various peptidesincreased the susceptibility ofGP libα to thrombin-induced proteolysis,as quantitated onpolyacryfamide gels.The order of potency of these peptides was RGDS<LGGAKQAGDV < KGDS < RGES. This order of potency agrees with that for the abilityof these peptides to inhibit 125I-fibrinogen binding to platelets. The effect of the peptides on proteolysis was time-, temperature-, and concentration-dependent; RGDS Induced a half-maximal effect at ˜60μM. Evaluation of the hydrodynamic properties of GP IIb-IIIa showed that LGGAKQAGDV orRGDS, but not RGES, decreased thesedimentation coefficient of GP IIb-IIIa from 8.5S to 7.7 S or7.4, S,respectively. This changewas accompanied by an increase in theStoke’s radius from 73 A to 84 A. These results suggestthat LGGAKQAGDV andRGDS alterthe conformationof the purified GPIIb-IIIa heterodimer complex by causing it to unfold.This change in conformation may be related to changesin the distribution and function of GP IIb-IIIaon the platelet surface that occurwith occupancy ofligand binding sites.

scholarly journals Linking function to global and local dynamics in an elevator-type transporter

2021 ◽  
Vol 118 (49) ◽  
pp. e2025520118
Author(s):  
Didar Ciftci ◽  
Chloe Martens ◽  
Vishnu G. Ghani ◽  
Scott C. Blanchard ◽  
Argyris Politis ◽  
...  
Keyword(s):  
Single Molecule ◽  
Conformational Changes ◽  
Structural Changes ◽  
Substrate Affinity ◽  
Substrate Uptake ◽  
Local Dynamics ◽  
Transport Efficiency ◽  
Temporal Relationships ◽  
And Function ◽  
Global And Local

Transporters cycle through large structural changes to translocate molecules across biological membranes. The temporal relationships between these changes and function, and the molecular properties setting their rates, determine transport efficiency—yet remain mostly unknown. Using single-molecule fluorescence microscopy, we compare the timing of conformational transitions and substrate uptake in the elevator-type transporter GltPh. We show that the elevator-like movements of the substrate-loaded transport domain across membranes and substrate release are kinetically heterogeneous, with rates varying by orders of magnitude between individual molecules. Mutations increasing the frequency of elevator transitions and reducing substrate affinity diminish transport rate heterogeneities and boost transport efficiency. Hydrogen deuterium exchange coupled to mass spectrometry reveals destabilization of secondary structure around the substrate-binding site, suggesting that increased local dynamics leads to faster rates of global conformational changes and confers gain-of-function properties that set transport rates.

scholarly journals Conformational dynamics of androgen receptors bound to agonists and antagonists

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hyo Jin Gim ◽  
Jiyong Park ◽  
Michael E. Jung ◽  
K. N. Houk
Keyword(s):  
Conformational Changes ◽  
Structural Changes ◽  
Structural Integrity ◽  
Structural Information ◽  
Close Contact ◽  
Conformational Dynamics ◽  
Principal Component ◽  
Binding Pocket ◽  
Structural Basis ◽  
Accelerated Molecular Dynamics

AbstractThe androgen receptor (AR) is critical in the progression of prostate cancer (PCa). Small molecule antagonists that bind to the ligand binding domain (LBD) of the AR have been successful in treating PCa. However, the structural basis by which the AR antagonists manifest their therapeutic efficacy remains unclear, due to the lack of detailed structural information of the AR bound to the antagonists. We have performed accelerated molecular dynamics (aMD) simulations of LBDs bound to a set of ligands including a natural substrate (dihydrotestosterone), an agonist (RU59063) and three antagonists (bicalutamide, enzalutamide and apalutamide) as well as in the absence of ligand (apo). We show that the binding of AR antagonists at the substrate binding pocket alter the dynamic fluctuations of H12, thereby disrupting the structural integrity of the agonistic conformation of AR. Two antagonists, enzalutamide and apalutamide, induce considerable structural changes to the agonist conformation of LBD, when bound close to H12 of AR LBD. When the antagonists bind to the pocket with different orientations having close contact with H11, no significant conformational changes were observed, suggesting the AR remains in the functionally activated (agonistic) state. The simulations on a drug resistance mutant F876L bound to enzalutamide demonstrated that the mutation stabilizes the agonistic conformation of AR LBD, which compromises the efficacy of the antagonists. Principal component analysis (PCA) of the structural fluctuations shows that the binding of enzalutamide and apalutamide induce conformational fluctuations in the AR, which are markedly different from those caused by the agonist as well as another antagonist, bicalutamide. These fluctuations could only be observed with the use of aMD.

NCIPLOT4: A New Step Towards a Fast Quantification of Noncovalent Interactions

2020 ◽  
Author(s):  
Roberto Boto ◽  
Francesca Peccati ◽  
Rubén Laplaza ◽  
chaoyu quan ◽  
Alessandra Carbone ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Structural Changes ◽  
Driving Forces ◽  
Noncovalent Interactions ◽  
Noncovalent Interaction ◽  
Simple Approach ◽  
Machine Learning Algorithms ◽  
Definition Of ◽  
And Function ◽  
The Relationship

<br>The quantification of noncovalent interactions in big systems is of crucial importance for understanding the structure and function of biosystems. The NCI method [J. Am. Chem. Soc. 132 , 6498 (2010)] enables to identify attractive and repulsive noncovalent interactions from promolecular densities in a fast manner. However, the approach remained up to now visual/qualitative, the relationship with energetics was conspicuously missing. We present a new version of NCIPLOT which allows quantifying the properties of the NonCovalent Interaction (NCI) regions in a fast manner. In order to do so, the definition of NCI volumes is introduced, which allows quantification of intra and intermolecular NCI properties in big systems where wavefunctions are not available. The connection between these integrals and energetics is reviewed for benchmark systems (S66 8), showing that our simple approach can lead to GGAquality energies while scaling with the number of atoms involved in the interaction (not the total number of atoms). The new implementation also includes an adaptive grid which allows the computation in a fast, parallelizable and efficient computational environment. The relationship with energetics derived from force fields is highlighted<br>and the faster algorithm exploited to analyze the evolution of interactions along MD trajectories. Through machine learning algorithms we characterize the relevance of NCI integrals in understanding the energetics of big systems, which is then applied in revealing the energetic changes along conformational changes, as well as identifying the atoms involved. This simple approach enables to identify the driving forces in biomolecular structural changes both at the spatial and energetic levels, while going beyond a mere parametrized-distances analysis.<br>

scholarly journals The effects of autolysis on the structure of chicken calpain II

1987 ◽  
Vol 248 (2) ◽  
pp. 579-588 ◽  
Author(s):  
C Crawford ◽  
A C Willis ◽  
J Gagnon
Keyword(s):  
Structural Changes ◽  
Structural Integrity ◽  
Large Subunit ◽  
Limited Proteolysis ◽  
Gel Permeation Chromatography ◽  
Enzymic Activity ◽  
Amino Acid Sequences ◽  
Cleavage Sites ◽  
Terminal Amino ◽  
Calpain Ii

When chicken calpain II autolysed in the presence of Ca2+, it underwent limited proteolysis to give peptides of Mr 54,000 and 37,000, and several of Mr approx. 30,000 and 18,000. The autolytic peptides were purified and their N-terminal amino acid sequences determined. By comparison of these sequences with the known sequence of the complete calpain molecule, the autolytic cleavage sites were identified. The structural integrity of the molecule during autolysis was investigated by gel-permeation chromatography. Experiments were also done to test the reversibility of adding EDTA to calpain during autolysis, measured as recoverable enzyme activity assayed in the presence of Ca2+. The results are presented in terms of a model for the structural changes occurring in calpain during autolysis. It was concluded that the loss of enzymic activity, which is a consequence of autolysis, was due to dissociation of the autolytic peptides after cleavage of the calpain large subunit within the third domain.

scholarly journals Abstract P-36: Structural Analysis of Conformational Changes of Bacterial and Eukaryotic Tubulins

2021 ◽  
Vol 11 (Suppl_1) ◽  
pp. S27-S28
Author(s):  
Liubov Makarova ◽  
Alena Korshunova
Keyword(s):  
Structural Analysis ◽  
Conformational Changes ◽  
Structural Changes ◽  
Dynamic Instability ◽  
Amino Acid Sequences ◽  
Anchor Point ◽  
Final State ◽  
Gtp Hydrolysis ◽  
Alpha Tubulin ◽  
Β Tubulin

Background: Eukaryotic α- and β-tubulin proteins stand out among tubulin-like proteins by their ability to form hollow dynamically unstable microtubules (MT) with 13 protofilaments. Microtubules are part of the cell cytoskeleton and play a key role in chromosome division in mitosis. A considerable amount of anticancer drugs works on microtubules level breaking its dynamic. But the mechanism of dynamic instability and works of these drugs remains unknown. Bacteria of the genus Prostecobacter have unique bacterial tubulins (BtubA/B) capable to form hollow dynamically unstable 5 protofilament MTs (miniMT). Instead of great differences, both tubulins have many common features. Eukaryotic tubulin was known to have structural changes through GTP hydrolysis (compactization for approximately 2 Å and a twist for 0,1˚). «Anchor point» structure in alpha-tubulin was noticed to be a fixed point in this movement. Methods: We performed comparative structural analysis of BtubA/B and α- and β-tubulin proteins using USCF Chimera10 and MEGA X software. This data was obtained due to a comparison of 3 structures of microtubules with different nucleotides [pdb6DPU, 6DPV, 6DPW] and two structures for bacterial tubulins (miniMT [pdb5o09] and BtubA/B-dimer [pdb2BTQ]). Results: We noticed that bacterial tubulins form shorter protofilaments in miniMT than eukaryotic ones. It can be explained as compaction in two sites instead of one site in eukaryotic MT. Also, the most motionless point of min MT turned out the same "anchor point." Phylogenetic analysis showed that this structure is very conservative in these orthologs. Moreover, the final state of both tubulins (GDP) repeats each other. Conclusion: Our results suggest that bacterial tubulin can have movements through GTP hydrolysis similar to eukaryotic one. And it means that despite different amino acid sequences, bacterial and eukaryotic tubulins have similar keys structures for dynamic instability.

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