Computational Modeling of the Virucidal Inhibition Mechanism for Broad-Spectrum Antiviral Nanoparticles and HPV16 Capsid Segments

Chaturvedi, Parth; Kelich, Payam; Nitka, Tara A.; Vuković, Lela

doi:10.1021/acs.jpcb.1c07436

Cited by 5 publications

(7 citation statements)

References 40 publications

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“…PFOA molecules were docked onto BLG using the AutoDock Vina software. , In our docking procedure, the grid box was centered at various positions on a grid with varying x -, y -, and z -coordinates with an interval of 5 nm. The docking was performed by scanning PFOA binding to the whole protein surface, using the automated procedure within our in-house Linux shell script (), which returns the ligand poses and their corresponding docking scores. The obtained PFOA ligand poses were analyzed using the gmx-cluster algorithm in the GROningen MAchine for Chemical Simulations (GROMACS) package .…”

Section: Experimental Materials and Methodsmentioning

confidence: 99%

An Atomic and Molecular Insight into How PFOA Reduces α-Helicity, Compromises Substrate Binding, and Creates Binding Pockets in a Model Globular Protein

Yadav,

Vuković,

Narayan

2024

J. Am. Chem. Soc.

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Per-and polyfluoroalkyl substances (PFAS) pose significant health risks due to their widespread presence in various environmental and biological matrices. However, the molecular-level mechanisms underlying the interactions between PFAS and biological constituents, including proteins, carbohydrates, lipids, and DNA, remain poorly understood. Here, we investigate the interactions between a legacy PFAS, viz. perfluorooctanoic acid (PFOA), and the milk protein β-lactoglobulin (BLG) obtained using a combination of experimental and computational techniques. Circular dichroism studies reveal that PFOA perturbs the secondary structure of BLG, by driving a dose-dependent loss of α-helicity and alterations in its β-sheet content. Furthermore, exposure of the protein to PFOA attenuates the on-rate constant for the binding of the hydrophobic probe 8anilino-1-naphthalene sulfonic acid (ANS), suggesting potential functional impairment of BLG by PFOA. Steered molecular dynamics and umbrella sampling calculations reveal that PFOA binding leads to the formation of an energetically favorable novel binding pocket within the protein, when residues 129−142 are steered to unfold from their initial α-helical structure, wherein a host of intermolecular interactions between PFOA and BLG's residues serve to insert the PFOA into the region between the unfolded helix and beta-sheets. Together, the data provide a novel understanding of the atomic and molecular mechanism(s) by which PFAS modulates structure and function in a globular protein, leading to a beginning of our understanding of altered biological outcomes.

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Section: Experimental Materials and Methodsmentioning

confidence: 99%

An Atomic and Molecular Insight into How PFOA Reduces α-Helicity, Compromises Substrate Binding, and Creates Binding Pockets in a Model Globular Protein

Yadav,

Vuković,

Narayan

2024

J. Am. Chem. Soc.

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“…38 In AutoDock Vina, the grid box was centered at various positions on a grid, scanning the protein surface with varying x, y, and z-coordinates with an interval of 1 nm. The docking procedure 39 was automated using an in-house Linux shell script (https://github.com/vukoviclab/docking-scan). Using this procedure, the docked ligands, namely, retinol and PS, are ranked according to the docking score.…”

Section: Molecular Docking Calculations and MD Simulationsmentioning

confidence: 99%

Interfacial Interactions between Nanoplastics and Biological Systems: toward an Atomic and Molecular Understanding of Plastics-Driven Biological Dyshomeostasis

Karim,

Yadav,

Sweety

et al. 2024

ACS Appl. Mater. Interfaces

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Micro- and nano-plastics (NPs) are found in human milk, blood, tissues, and organs and associate with aberrant health outcomes including inflammation, genotoxicity, developmental disorders, onset of chronic diseases, and autoimmune disorders. Yet, interfacial interactions between plastics and biomolecular systems remain underexplored. Here, we have examined experimentally, in vitro, in vivo, and by computation, the impact of polystyrene (PS) NPs on a host of biomolecular systems and assemblies. Our results reveal that PS NPs essentially abolished the helix-content of the milk protein β-lactoglobulin (BLG) in a dose-dependent manner. Helix loss is corelated with the near stoichiometric formation of β-sheet elements in the protein. Structural alterations in BLG are also likely responsible for the nanoparticle-dependent attrition in binding affinity and weaker on-rate constant of retinol, its physiological ligand (compromising its nutritional role). PS NP-driven helix-to-sheet conversion was also observed in the amyloid-forming trajectory of hen egg-white lysozyme (accelerated fibril formation and reduced helical content in fibrils). Caenorhabditis elegans exposed to PS NPs exhibited a decrease in the fluorescence of green fluorescent protein-tagged dopaminergic neurons and locomotory deficits (akin to the neurotoxin paraquat exposure). Finally, in silico analyses revealed that the most favorable PS/BLG docking score and binding energies corresponded to a pose near the hydrophobic ligand binding pocket (calyx) of the protein where the NP fragment was found to make nonpolar contacts with side-chain residues via the hydrophobic effect and van der Waals forces, compromising side chain/retinol contacts. Binding energetics indicate that PS/BLG interactions destabilize the binding of retinol to the protein and can potentially displace retinol from the calyx region of BLG, thereby impairing its biological function. Collectively, the experimental and high-resolution in silico data provide new insights into the mechanism(s) by which PS NPs corrupt the bimolecular structure and function, induce amyloidosis and onset neuronal injury, and drive aberrant physiological and behavioral outcomes.

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“…Virustatic antivirals could block individual viral proteins involved in the virulence [10]. In contrast, virucidal antivirals might act as strong multivalent binders to multiple receptor proteins positioned on the viral surface, thereby destabilizing the entire virus [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Sulfoglycodendron Antivirals with Scalable Architectures and Activities

Coppola,

Jafari,

McReynolds

et al. 2024

Preprint

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Many viruses initiate their cell-entry by binding their multi-protein receptors to human heparan sulfate proteoglycans (HSPG) and other molecular components present on cellular membranes. These viral interactions could be blocked and the whole viruses could be eliminated by suitable HSPG-mimetics providing multivalent binding to viral protein receptors. Here, large sulfoglyco-dendron HSPG-mimetics of different topologies, structures, and sizes were designed to this purpose. Atomistic molecular dynamics simulations were used to examine the ability of these broad-spectrum antivirals to block multi-protein HSPG-receptors in HIV, SARS-CoV-2, HPV, and dengue viruses. To characterize the inhibitory potential of these mimetics, their binding to individual and multiple protein receptors was examined. In particular, vectorial distributions of binding energies between the mimetics and viral protein receptors were introduced and calculated along the simulated trajectories. Space-dependent residual analysis of the mimetic-receptor binding was also performed. This analysis revealed detail nature of binding between these antivirals and viral protein receptors, and provided evidence that large inhibitors with multivalent binding might act like a molecular glue initiating the self-assembly of protein receptors in enveloped viruses.

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Computational Modeling of the Virucidal Inhibition Mechanism for Broad-Spectrum Antiviral Nanoparticles and HPV16 Capsid Segments

Cited by 5 publications

References 40 publications

An Atomic and Molecular Insight into How PFOA Reduces α-Helicity, Compromises Substrate Binding, and Creates Binding Pockets in a Model Globular Protein

An Atomic and Molecular Insight into How PFOA Reduces α-Helicity, Compromises Substrate Binding, and Creates Binding Pockets in a Model Globular Protein

Interfacial Interactions between Nanoplastics and Biological Systems: toward an Atomic and Molecular Understanding of Plastics-Driven Biological Dyshomeostasis

Sulfoglycodendron Antivirals with Scalable Architectures and Activities

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