scholarly journals Impact of the Position of the Chemically Modified 5-Furyl-2′-Deoxyuridine Nucleoside on the Thrombin DNA Aptamer–Protein Complex: Structural Insights into Aptamer Response from MD Simulations

Molecules ◽  
2019 ◽  
Vol 24 (16) ◽  
pp. 2908 ◽  
Author(s):  
Preethi Seelam Prabhakar ◽  
Richard A. Manderville ◽  
Stacey D. Wetmore
Keyword(s):  
Binding Affinity ◽  
Structural Changes ◽  
Experimental Studies ◽  
Local Environment ◽  
Md Simulations ◽  
Fine Tuning ◽  
Dna Aptamer ◽  
Solvent Exposure ◽  
Chemically Modified ◽  
Target Binding

Aptamers are functional nucleic acids that bind to a range of targets (small molecules, proteins or cells) with a high affinity and specificity. Chemically-modified aptamers are of interest because the incorporation of novel nucleobase components can enhance aptamer binding to target proteins, while fluorescent base analogues permit the design of functional aptasensors that signal target binding. However, since optimally modified nucleoside designs have yet to be identified, information about how to fine tune aptamer stability and target binding affinity is required. The present work uses molecular dynamics (MD) simulations to investigate modifications to the prototypical thrombin-binding aptamer (TBA), which is a 15-mer DNA sequence that folds into a G-quadruplex structure connected by two TT loops and one TGT loop. Specifically, we modeled a previously synthesized thymine (T) analog, namely 5-furyl-2′-deoxyuridine (5FurU), into each of the six aptamer locations occupied by a thymine base in the TT or TGT loops of unbound and thrombin bound TBA. This modification and aptamer combination were chosen as a proof-of-principle because previous experimental studies have shown that TBA displays emissive sensitivity to target binding based on the local environment polarity at different 5FurU modification sites. Our simulations reveal that the chemically-modified base imparts noticeable structural changes to the aptamer without affecting the global conformation. Depending on the modification site, 5FurU performance is altered due to changes in the local environment, including the modification site structural dynamics, degree of solvent exposure, stacking with neighboring bases, and interactions with thrombin. Most importantly, these changes directly correlate with the experimentally-observed differences in the stability, binding affinity and emissive response of the modified aptamers. Therefore, the computational protocols implemented in the present work can be used in subsequent studies in a predictive way to aid the fine tuning of aptamer target recognition for use as biosensors (aptasensors) and/or therapeutics.

Manipulation of a DNA aptamer–protein binding site through arylation of internal guanine residues

2018 ◽  
Vol 16 (20) ◽  
pp. 3831-3840 ◽  
Author(s):  
Abigail J. Van Riesen ◽  
Kaila L. Fadock ◽  
Prashant S. Deore ◽  
Ahmed Desoky ◽  
Richard A. Manderville ◽  
...  
Keyword(s):  
Protein Binding ◽  
Binding Site ◽  
Binding Affinity ◽  
Target Recognition ◽  
Molecular Target ◽  
Dna Aptamer ◽  
Protein Binding Site ◽  
Chemically Modified ◽  
Structure Activity ◽  
Target Binding

Chemically modified aptamers have the opportunity to increase aptamer target binding affinity and provide structure–activity relationships to enhance our understanding of molecular target recognition by the aptamer fold.

scholarly journals Study on the influence of G82S RAGE polymorphism on RAGE-Amyloid interaction in AD pathology

2019 ◽  
Author(s):  
Rani Cathrine. C ◽  
Bincy Lukose ◽  
P. Rani
Keyword(s):  
Cell Line ◽  
Binding Affinity ◽  
Structural Changes ◽  
Md Simulations ◽  
Binding Pocket ◽  
Enhanced Expression ◽  
Shsy5y Cell ◽  
High Affinity Receptor ◽  
Aβ42 Peptide

AbstractReceptor for advanced glycation end products (RAGE) has been implicated in the pathophysiology of AD due to its ability to bind amyloid-beta and mediate inflammatory response. G82S RAGE polymorphism is associated with AD but the molecular mechanism for this association is not understood. Our previous in silico study indicated a higher binding affinity for mutated G82S RAGE, which could be caused due to changes in N linked glycosylation at residue N81. To confirm this hypothesis, in the present study molecular dynamics (MD) simulations were used to simulate the wild type (WT) and G82S glycosylated structures of RAGE to identify the global structural changes and to find the binding efficiency with Aβ42 peptide. Binding pocket analysis of the MD trajectory showed that cavity/binding pocket in mutant G82S glycosylated RAGE variants is more exposed and accessible to external ligands compared to WT RAGE, which can enhance the affinity of RAGE for Aβ. To validate the above concept, an in vitro binding study was carried using SHSY5Y cell line expressing recombinant WT and mutated RAGE variant individually to which HiLyte Fluor labeled Aβ42 was incubated at different concentrations. Saturated binding kinetics method was adopted to determine the Kd values for Aβ42 binding to RAGE. The Kd value for Aβ42-WT and Aβ42-mutant RAGE binding were 92±40 nM (95% CI-52 to 152nM; R2-0.92) and 45±20 nM (95% CI −29 to 64nM; R2-0.93), respectively. The Kd value of <100nM observed for both variants implicates RAGE as a high-affinity receptor for Aβ42 and mutant RAGE has higher affinity compared to WT. The alteration in binding affinity is responsible for activation of the inflammatory pathway as implicated by enhanced expression of TNFα and IL6 in mutant RAGE expressing cell line which gives a mechanistic view for the G82S RAGE association with AD.

scholarly journals Quantifying the adhesive strength between the SARS-CoV-2 S-proteins and human receptor and its effect in therapeutics

2020 ◽  
Author(s):  
Mauricio Ponga de la Torre
Keyword(s):  
Binding Energy ◽  
Binding Affinity ◽  
Adhesive Strength ◽  
Computational Design ◽  
Md Simulations ◽  
Adhesive Force ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Target Binding ◽  
S Proteins

Abstract The binding affinity and adhesive strength between the spike (S) glycoproteins of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the human angiotensin-converting enzyme 2 (ACE2) receptor is computed using molecular dynamics (MD) simulations. The calculations indicate that the binding affinity is e RS = 12.6 ± 1 kCal∙mol-1 with a maximum adhesive force of ~102 pN. Our analysis suggests that only 27 (13 in S-protein, 14 in ACE2) residues are active during the initial fusion process between the S-protein and ACE2 receptor. With these insights, we investigated the effect of possible therapeutics in the size and wrapping time of virus particles by reducing the binding energy. Our analysis indicates that this energy has to be reduced significantly, around 50% or more, to block SARS-CoV-2 particles with radius in the order of R≤60 nm. Our study provides concise target residues and target binding energy reduction between S-proteins and receptors for the development of new therapeutics treatments for COVID-19 guided by computational design.

scholarly journals Quantifying the adhesive strength between the SARS-CoV-2 S-proteins and human receptor and its effect in therapeutics

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Mauricio Ponga
Keyword(s):  
Binding Energy ◽  
Binding Affinity ◽  
Adhesive Strength ◽  
Computational Design ◽  
Md Simulations ◽  
Adhesive Force ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Target Binding ◽  
S Proteins

Abstract The binding affinity and adhesive strength between the spike (S) glycoproteins of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the human angiotensin-converting enzyme 2 (ACE2) receptor is computed using molecular dynamics (MD) simulations. The calculations indicate that the binding affinity is $$e_{RS}= 12.6 \pm 1$$ e RS = 12.6 ± 1 $$\hbox {kCal}{\cdot }\hbox {mol}^{-1}$$ kCal · mol - 1 with a maximum adhesive force of $$\sim 102$$ ∼ 102 pN. Our analysis suggests that only 27 (13 in S-protein, 14 in ACE2) residues are active during the initial fusion process between the S-protein and ACE2 receptor. With these insights, we investigated the effect of possible therapeutics in the size and wrapping time of virus particles by reducing the binding energy. Our analysis indicates that this energy has to be reduced significantly, around 50% or more, to block SARS-CoV-2 particles with radius in the order of $$R\le 60$$ R ≤ 60 nm. Our study provides concise target residues and target binding energy reduction between S-proteins and receptors for the development of new therapeutics treatments for COVID-19 guided by computational design.

scholarly journals Quantifying the adhesive strength between the SARS-CoV-2 S-proteins and human receptor and its effect in therapeutics

2020 ◽  
Author(s):  
Mauricio Ponga de la Torre
Keyword(s):  
Binding Energy ◽  
Binding Affinity ◽  
Adhesive Strength ◽  
Computational Design ◽  
Md Simulations ◽  
Adhesive Force ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Target Binding ◽  
S Proteins

Abstract The binding affinity and adhesive strength between the spike (S) glycoproteins of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the human angiotensin-converting enzyme 2 (ACE2) receptor is computed using molecular dynamics (MD) simulations. The calculations indicate that the binding affinity is eRS= 12.6 +/- 1 kCal mol-1 with a maximum adhesive force of ~102 pN. Our analysis suggests that only 27 (13 in S-protein, 14 in ACE2) residues are active during the initial fusion process between the S-protein and ACE2 receptor. With these insights, we investigated the effect of possible therapeutics in the size and wrapping time of virus particles by reducing the binding energy. Our analysis indicates that this energy has to be reduced significantly, around 50\% or more, to block SARS-CoV-2 particles with radius in the order of R < 60 nm. Our study provides concise target residues and target binding energy reduction between S-proteins and receptors for the development of new therapeutics treatments for COVID-19 guided by computational design.

Analysis of the results of medium-energy electrons on the protective and thermoregulatory coatings of high-orbit satellites

2018 ◽  
pp. 156-171
Author(s):  
A. M. Shamayev ◽  
M. D. Ozersky
Keyword(s):  
Structural Changes ◽  
Protective Coatings ◽  
Experimental Studies ◽  
Thermal Control ◽  
Space Vehicles ◽  
Medium Energy ◽  
Electrostatic Discharges ◽  
High Orbit ◽  
Thermal Control Coatings ◽  
Solar Batteries

The results of experimental studies of the effect of electron irradiation on K-208 and CMG glasses used for manufacturing protective coatings of solar batteries and thermal control coatings of space vehicles are analyzed. It is shown that the caused electrostatic discharges lead to structural changes in the surfaces of the glasses studied. The goals of further studies of the influence of proton and electronproton effects on the properties of such coatings are outlined. 

scholarly journals Multi-Targeting Bioactive Compounds Extracted from Essential Oils as Kinase Inhibitors

Molecules ◽  
2020 ◽  
Vol 25 (9) ◽  
pp. 2174 ◽  
Author(s):  
Annalisa Maruca ◽  
Delia Lanzillotta ◽  
Roberta Rocca ◽  
Antonio Lupia ◽  
Giosuè Costa ◽  
...  
Keyword(s):  
Essential Oils ◽  
Binding Affinity ◽  
Structural Changes ◽  
Kinase Inhibitors ◽  
Synergistic Effects ◽  
Data Bank ◽  
Binding Modes ◽  
Starting Point ◽  
Target Action ◽  
Potential Resource

Essential oils (EOs) are popular in aromatherapy, a branch of alternative medicine that claims their curative effects. Moreover, several studies reported EOs as potential anti-cancer agents by inducing apoptosis in different cancer cell models. In this study, we have considered EOs as a potential resource of new kinase inhibitors with a polypharmacological profile. On the other hand, computational methods offer the possibility to predict the theoretical activity profile of ligands, discovering dangerous off-targets and/or synergistic effects due to the potential multi-target action. With this aim, we performed a Structure-Based Virtual Screening (SBVS) against X-ray models of several protein kinases selected from the Protein Data Bank (PDB) by using a chemoinformatics database of EOs. By evaluating theoretical binding affinity, 13 molecules were detected among EOs as new potential kinase inhibitors with a multi-target profile. The two compounds with higher percentages in the EOs were studied more in depth by means Induced Fit Docking (IFD) protocol, in order to better predict their binding modes taking into account also structural changes in the receptor. Finally, given its good binding affinity towards five different kinases, cinnamyl cinnamate was biologically tested on different cell lines with the aim to verify the antiproliferative activity. Thus, this work represents a starting point for the optimization of the most promising EOs structure as kinase inhibitors with multi-target features.

scholarly journals Inhibition of MMP2-PEX by a novel ester of dihydroxy cinnamic and linoleic acid from the seagrass Cymodocea serrulata

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
V. S. Christina ◽  
R. Lakshmi Sundaram ◽  
V. Sivamurugan ◽  
D. Thirumal Kumar ◽  
C. D. Mohanapriya ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Ovarian Cancer Cell Line ◽  
Cancer Cell Line ◽  
Md Simulations ◽  
Cell Types ◽  
Structural Details ◽  
M Phase ◽  
Ft Ir ◽  
Target Binding ◽  
Cymodocea Serrulata

AbstractMatrix metalloproteinases (MMPs) are pivotal for cancer cell migration and metastasis which are generally over-expressed in such cell types. Many drugs targeting MMPs do so by binding to the conserved catalytic domains and thus exhibit poor selectivity due to domain-similarities with other proteases. We report herein the binding of a novel compound [3-(E-3,4-dihydroxycinnamaoyloxyl)-2-hydroxypropyl 9Z, 12Z-octadeca-9, 12-dienoate; Mol. wt: 516.67 Da], (C1), isolated from a seagrass, Cymodocea serrulata to the unconserved hemopexin-like (PEX) domain of MMP2 (− 9.258 kcal/mol). MD simulations for 25 ns, suggest stable ligand-target binding. In addition, C1 killed an ovarian cancer cell line, PA1 at IC50: 5.8 μM (lesser than Doxorubicin: 8.6 µM) and formed micronuclei, apoptotic bodies and nucleoplasmic bridges whilst causing DNA laddering, S and G2/M phase dual arrests and MMP disturbance, suggesting intrinsic apoptosis. The molecule increased mRNA transcripts of BAX and BAD and down-regulated cell survival genes, Bcl-xL, Bcl-2, MMP2 and MMP9. The chemical and structural details of C1 were deduced through FT-IR, GC–MS, ESI–MS, 1H and 13C NMR [both 1D and 2D] spectra.

scholarly journals Herb-target virtual screening and network pharmacology for prediction of molecular mechanism of Danggui Beimu Kushen Wan for prostate cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hong Li ◽  
Andrew Hung ◽  
Angela Wei Hong Yang
Keyword(s):  
Prostate Cancer ◽  
Binding Affinity ◽  
Molecular Mechanisms ◽  
Biological Activities ◽  
Tight Binding ◽  
Experimental Studies ◽  
Network Pharmacology ◽  
High Morbidity ◽  
High Binding ◽  
High Binding Affinity

AbstractProstate cancer (PCa) is a cancer that occurs in the prostate with high morbidity and mortality. Danggui Beimu Kushen Wan (DBKW) is a classic formula for patients with difficult urination including PCa. This study aimed to investigate the molecular mechanisms of DBKW for PCa. We obtained DBKW compounds from our previous reviews. We identified potential targets for PCa from literature search, currently approved drugs and Open Targets database and filtered them by protein–protein interaction network analysis. We selected 26 targets to predict three cancer-related pathways. A total of 621 compounds were screened via molecular docking using PyRx and AutoDock Vina against 21 targets for PCa, producing 13041 docking results. The binding patterns and positions showed that a relatively small number of tight-binding compounds from DBKW were predicted to interact strongly and selectively with three targets. The top five high-binding-affinity compounds were selected to generate a network, indicating that compounds from all three herbs had high binding affinity against the 21 targets and may have potential biological activities with the targets. DBKW contains multi-targeting agents that could act on more than one pathway of PCa simultaneously. Further studies could focus on validating the computational results via experimental studies.

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.

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