SARS-Cov-2 Delta Variant Decreases Nanobody Binding and ACE2 Blocking Effectivity

2021 ◽  
Author(s):  
Mert Golcuk ◽  
Aysima Hacisuleyman ◽  
Sema Zeynep Yilmaz ◽  
Elhan Taka ◽  
Ahmet Yildiz ◽  
...  
Keyword(s):  
Hydrophobic Interactions ◽  
Salt Bridge ◽  
Md Simulations ◽  
Host Cells ◽  
Receptor Binding Domain ◽  
Angiotensin Converting Enzyme 2 ◽  
Force Microscopy ◽  
Loading Rates ◽  
Atomic Force ◽  
New Generation

The Delta variant spreads more rapidly than previous variants of SARS-CoV-2. This variant comprises several mutations on the receptor-binding domain (RBD_Delta) of its spike (S) glycoprotein, which binds to the peptidase domain (PD) of angiotensin-converting enzyme 2 (ACE2) receptors in host cells. The RBD-PD interaction has been targeted by antibodies and nanobodies to prevent viral infection, but their effectiveness against the Delta variant remains unclear. Here, we investigated RBD_Delta-PD interactions in the presence and absence of nanobodies H11-H4, H11-D4, and Ty1 by performing in a total of 19 µs all-atom molecular dynamics (MD) simulations. Unbiased simulations revealed that Delta variant mutations strengthen RBD binding to ACE2 by increasing the hydrophobic interactions and salt bridge formation, but weaken interactions with H11-H4, H11-D4, and Ty1. Consequently, these nanobodies are unable to dislocate ACE2 from RBD_Delta. Steered MD simulations at comparable loading rates to atomic force microscopy (AFM) experiments estimated lower rupture forces of the nanobodies from RBD_Delta compared to ACE2. Our results suggest that existing nanobodies are less effective to inhibit RBD_Delta-PD interactions and a new generation of nanobodies will be needed to neutralize the Delta variant.

scholarly journals Molecular interaction and inhibition of SARS-CoV-2 binding to the ACE2 receptor

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jinsung Yang ◽  
Simon J. L. Petitjean ◽  
Melanie Koehler ◽  
Qingrong Zhang ◽  
Andra C. Dumitru ◽  
...  
Keyword(s):  
Binding Pocket ◽  
Living Cells ◽  
Host Cells ◽  
The Novel ◽  
Angiotensin Converting Enzyme 2 ◽  
Force Microscopy ◽  
Binding Interface ◽  
Atomic Force ◽  
Viral Glycoproteins ◽  
Novel Coronavirus

Abstract Study of the interactions established between the viral glycoproteins and their host receptors is of critical importance for a better understanding of virus entry into cells. The novel coronavirus SARS-CoV-2 entry into host cells is mediated by its spike glycoprotein (S-glycoprotein), and the angiotensin-converting enzyme 2 (ACE2) has been identified as a cellular receptor. Here, we use atomic force microscopy to investigate the mechanisms by which the S-glycoprotein binds to the ACE2 receptor. We demonstrate, both on model surfaces and on living cells, that the receptor binding domain (RBD) serves as the binding interface within the S-glycoprotein with the ACE2 receptor and extract the kinetic and thermodynamic properties of this binding pocket. Altogether, these results provide a picture of the established interaction on living cells. Finally, we test several binding inhibitor peptides targeting the virus early attachment stages, offering new perspectives in the treatment of the SARS-CoV-2 infection.

scholarly journals Millisecond-scale molecular dynamics simulation of spike RBD structure reveals evolutionary adaption of SARS-CoV-2 to stably bind ACE2

2020 ◽  
Author(s):  
Gard Nelson ◽  
Oleksandr Buzko ◽  
Aaron Bassett ◽  
Patricia R Spilman ◽  
Kayvan Niazi ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Md Simulations ◽  
Host Cells ◽  
Dynamics Simulation ◽  
Receptor Binding Domain ◽  
Binding Region ◽  
Angiotensin Converting Enzyme 2 ◽  
Molecular Binding ◽  
Relative Affinity ◽  
Therapeutic Development

The Receptor Binding Domain (RBD) of the SARS-CoV-2 surface spike (S) protein interacts with host angiotensin converting enzyme 2 (ACE2) to gain entry to host cells and initiate infection 1-3. Detailed, accurate understanding of key interactions between S RBD and ACE2 provides critical information that may be leveraged in the development of strategies for the prevention and treatment of COVID-19. Utilizing the published sequences and cryo-EM structures of both the viral S RBD and ACE2 4,5, we performed in silico molecular dynamics (MD) simulations of free S RBD and of its interaction with ACE2 over the exceptionally long durations of 2.9 and 2 milliseconds, respectively, to elucidate the nature and relative affinity of S RBD surface residues for the ACE2 binding region. Our findings reveal that free S RBD has assumed an optimized ACE2 binding-ready conformation, incurring little entropic penalty for binding, an evolutionary adaptation that contributes to its high affinity for the receptor 6. We further identified high probability molecular binding interactions that inform both vaccine design and therapeutic development, which may include recombinant ACE2-based spike decoys 7 and/or allosteric S RBD-ACE2 binding inhibitors 8,9 to prevent or arrest infection and thus disease.

scholarly journals Molecular interaction and inhibition of SARS-CoV-2 binding to the ACE2 receptor

2020 ◽  
Author(s):  
Jinsung Yang ◽  
Simon Petitjean ◽  
Sylvie Derclaye ◽  
Melanie Koehler ◽  
Qingrong Zhang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Binding Pocket ◽  
Host Cells ◽  
The Novel ◽  
Angiotensin Converting Enzyme 2 ◽  
Force Microscopy ◽  
Binding Interface ◽  
Atomic Force ◽  
Viral Glycoproteins ◽  
Novel Coronavirus

Abstract Study of virus entry into cells is of critical importance for a better understanding of the interactions established between the viral glycoproteins and their receptors at the cell surface and could help to develop novel antiviral strategies. The novel coronavirus (SARS-CoV-2) entry into host cells is mediated by the transmembrane spike glycoprotein (S-glycoprotein) and the angiotensin-converting enzyme 2 (ACE2) has been identified as a cellular receptor. Here, we used atomic force microscopy to investigate the molecular mechanisms by which the S- glycoprotein binds to the ACE2 receptor. We demonstrated, both on model surfaces and on living cells, that the receptor binding domain (RBD) serves as a binding interface within the S- glycoprotein with the ACE2 receptor and we extracted the kinetic and thermodynamic properties of this binding pocket. Altogether, these results give a dynamic picture of the established interaction in physiologically relevant conditions. Finally, we identified and tested several binding inhibitor peptides targeting the virus early attachment stages, offering new perspectives in the treatment of the SARS-CoV-2 infection.

scholarly journals Molecular Mechanism of the N501Y Mutation for Enhanced Binding between SARS-CoV-2’s Spike Protein and Human ACE2 Receptor

2021 ◽  
Author(s):  
Binquan Luan ◽  
Haoran Wang ◽  
Tien Huynh
Keyword(s):  
Molecular Mechanism ◽  
Hydrophobic Interactions ◽  
Neutralizing Antibody ◽  
Host Cells ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Angiotensin Converting Enzyme 2 ◽  
Global Pandemic ◽  
Dynamics Simulations ◽  
Antibody Cocktail

AbstractCoronavirus disease 2019 (COVID-19) has been an ongoing global pandemic for over a year. Recently, an emergent SARS-CoV-2 variant (B.1.1.7) with an unusually large number of mutations had become highly contagious and wide-spreading in United Kingdom. From genome analysis, the N501Y mutation within the receptor binding domain (RBD) of the SARS-CoV-2’s spike protein might have enhanced the viral protein’s binding with the human angiotensin converting enzyme 2 (hACE2). The latter is the prelude for the virus’ entry into host cells. So far, the molecular mechanism of this enhanced binding is still elusive, which prevents us from assessing its effects on existing therapeutic antibodies. Using all atom molecular dynamics simulations, we demonstrated that Y501 in mutated RBD can be well coordinated by Y41 and K353 in hACE2 through hydrophobic interactions, increasing the overall binding affinity between RBD and hACE2 by about 0.81 kcal/mol. We further explored how the N501Y mutation might affect the binding between a neutralizing antibody (CB6) and RBD. We expect that our work can help researchers design proper measures responding to this urgent virus mutation, such as adding a modified/new neutralizing antibody specifically targeting at this variant in the therapeutic antibody cocktail.Abstract Figure

Targeting Breast Cancer Cells with G4 PAMAM Dendrimers and Valproic Acid Derivative Complexes

2020 ◽  
Vol 20 (15) ◽  
pp. 1857-1872
Author(s):  
Alberto M. Muñoz ◽  
Manuel J. Fragoso-Vázquez ◽  
Berenice P. Martel ◽  
Alma Chávez-Blanco ◽  
Alfonso Dueñas-González ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Cell Lines ◽  
Water Solubility ◽  
Md Simulations ◽  
Pamam Dendrimer ◽  
Pamam Dendrimers ◽  
Force Microscopy ◽  
Micromolar Concentration ◽  
Atomic Force

Background: Our research group has developed some Valproic Acid (VPA) derivatives employed as anti-proliferative compounds targeting the HDAC8 enzyme. However, some of these compounds are poorly soluble in water. Objective: Employed the four generations of Polyamidoamine (G4 PAMAM) dendrimers as drug carriers of these compounds to increase their water solubility for further in vitro evaluation. Methods: VPA derivatives were subjected to Docking and Molecular Dynamics (MD) simulations to evaluate their affinity on G4 PAMAM. Then, HPLC-UV/VIS, 1H NMR, MALDI-TOF and atomic force microscopy were employed to establish the formation of the drug-G4 PAMAM complexes. Results: The docking results showed that the amide groups of VPA derivatives make polar interactions with G4 PAMAM, whereas MD simulations corroborated the stability of the complexes. HPLC UV/VIS experiments showed an increase in the drug water solubility which was found to be directly proportional to the amount of G4 PAMAM. 1H NMR showed a disappearance of the proton amine group signals, correlating with docking results. MALDI-TOF and atomic force microscopy suggested the drug-G4 PAMAM dendrimer complexes formation. Discussion: In vitro studies showed that G4 PAMAM has toxicity in the micromolar concentration in MDAMB- 231, MCF7, and 3T3-L1 cell lines. VPA CF-G4 PAMAM dendrimer complex showed anti-proliferative properties in the micromolar concentration in MCF-7 and 3T3-L1, and in the milimolar concentration in MDAMB- 231, whereas VPA MF-G4 PAMAM dendrimer complex didn’t show effects on the three cell lines employed. Conclusion: These results demonstrate that G4 PAMAM dendrimers are capableof transporting poorly watersoluble aryl-VPA derivate compounds to increase its cytotoxic activity against neoplastic cell lines.

Rate dependence of serrated flow in a metallic glass

2003 ◽  
Vol 18 (4) ◽  
pp. 755-757 ◽  
Author(s):  
W. H. Jiang ◽  
M. Atzmon
Keyword(s):  
Plastic Deformation ◽  
Atomic Force Microscopy ◽  
Loading Rate ◽  
Shear Bands ◽  
Shear Band Formation ◽  
Band Formation ◽  
Serrated Flow ◽  
Force Microscopy ◽  
Loading Rates ◽  
Atomic Force

Plastic deformation of amorphous Al90Fe5Gd5 was investigated using nanoindentation and atomic force microscopy. While serrated flow was detected only at high loading rates, shear bands were observed for all loading rates, ranging from 1 to 100 nm/s. However, the details of shear-band formation depend on the loading rate.

scholarly journals Layered calcium phenylphosphonate: a hybrid material for a new generation of nanofillers

2018 ◽  
Vol 9 ◽  
pp. 2906-2915 ◽  
Author(s):  
Kateřina Kopecká ◽  
Ludvík Beneš ◽  
Klára Melánová ◽  
Vítězslav Zima ◽  
Petr Knotek ◽  
...  
Keyword(s):  
Mechanical Analysis ◽  
Gas Permeation ◽  
Synthesis Methods ◽  
X Ray Diffraction ◽  
Promising Technique ◽  
Force Microscopy ◽  
Atomic Force ◽  
Strong Shear ◽  
New Generation ◽  
Composite Properties

The use of nanosheets of layered calcium phenylphosphonate as a filler in a polymeric matrix was investigated. Layered calcium phenylphosphonate (CaPhP), with chemical formula CaC6H5PO3∙2H2O, is a hybrid organic–inorganic material that exhibits a hydrophobic character due to the presence of phenyl groups on the surface of the layers. In this paper, various CaPhP synthesis methods were studied with the aim of obtaining a product most suitable for its subsequent exfoliation. The liquid-based approach was used for the exfoliation. It was found that the most promising technique for the exfoliation of CaPhP in an amount sufficient for incorporation into polymers involved using propan-2-ol with a strong shear force generated in a high-shear disperser. The filler was tested both in its unexfoliated and exfoliated forms for the preparation of polymer composites, for which a low molecular weight epoxy resin based on bisphenol A was used as a polymer matrix. The prepared samples were characterized by powder X-ray diffraction, atomic force microscopy, optical and scanning electron microscopy, and dynamic mechanical analysis. Flammability and gas permeation tests were also performed. The addition of the nanofiller was found to influence the composite properties – the exfoliated particles were found to have a higher impact on the properties of the prepared composites than the unexfoliated particles of the same loading

scholarly journals Three-dimensional solvation structure of ethanol on carbonate minerals

2020 ◽  
Vol 11 ◽  
pp. 891-898
Author(s):  
Hagen Söngen ◽  
Ygor Morais Jaques ◽  
Peter Spijker ◽  
Christoph Marutschke ◽  
Stefanie Klassen ◽  
...  
Keyword(s):  
Specific Binding ◽  
Qualitative Difference ◽  
Three Dimensional ◽  
Md Simulations ◽  
General Nature ◽  
Surface Restructuring ◽  
Data Set ◽  
Force Microscopy ◽  
Atomic Force ◽  
Solid Liquid

Calcite and magnesite are important mineral constituents of the earth’s crust. In aqueous environments, these carbonates typically expose their most stable cleavage plane, the (10.4) surface. It is known that these surfaces interact with a large variety of organic molecules, which can result in surface restructuring. This process is decisive for the formation of biominerals. With the development of 3D atomic force microscopy (AFM) it is now possible to image solid–liquid interfaces with unprecedented molecular resolution. However, the majority of 3D AFM studies have been focused on the arrangement of water at carbonate surfaces. Here, we present an analysis of the assembly of ethanol – an organic molecule with a single hydroxy group – at the calcite and magnesite (10.4) surfaces by using high-resolution 3D AFM and molecular dynamics (MD) simulations. Within a single AFM data set we are able to resolve both the first laterally ordered solvation layer of ethanol on the calcite surface as well as the following solvation layers that show no lateral order. Our experimental results are in excellent agreement with MD simulations. The qualitative difference in the lateral order can be understood by the differing chemical environment: While the first layer adopts specific binding positions on the ionic carbonate surface, the second layer resides on top of the organic ethyl layer. A comparison of calcite and magnesite reveals a qualitatively similar ethanol arrangement on both carbonates, indicating the general nature of this finding.

Characterization of Hydrophobic Forces for in Liquid Self-Assembly of Micron-Sized Functional Building Blocks

2011 ◽  
Vol 1299 ◽  
Author(s):  
M. R. Gullo ◽  
L. Jacot-Descombes ◽  
L. Aeschimann ◽  
J. Brugger
Keyword(s):  
Atomic Force Microscopy ◽  
Self Assembly ◽  
Hydrophobic Interactions ◽  
Numerical Study ◽  
Building Blocks ◽  
Dynamic Simulations ◽  
Hydrophobic Force ◽  
Force Microscopy ◽  
Molecular Arrangement ◽  
Atomic Force

ABSTRACTThis paper presents the experimental and numerical study of hydrophobic interaction forces at nanometer scale in the scope of engineering micron-sized building blocks for self-assembly in liquid. The hydrophobic force distance relation of carbon, Teflon and dodeca-thiols immersed in degassed and deionized water has been measured by atomic force microscopy. Carbon and dodeca-thiols showed comparable attractive and binding forces in the rage of pN/nm2. Teflon showed the weakest binding and no attractive force. Molecular dynamic simulations were performed to correlate the molecular arrangement of water molecules and the hydrophobic interactions measured by atomic force microscopy. The simulations showed a depletion zone of 2Å followed by a layered region of 8Å in the axis perpendicular to the hydrophobic surface.

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