The Mechanism of Action for Drugs that Undermine HIV-1 Viral Capsid Formation and Activity: Insights from Large-Scale Coarse-Grained Simulations

ABSTRACT Cosmic reionization was driven by the imbalance between early sources and sinks of ionizing radiation, both of which were dominated by small-scale structure and are thus usually treated in cosmological reionization simulations by subgrid modelling. The recombination rate of intergalactic hydrogen is customarily boosted by a subgrid clumping factor, 〈n2〉/〈n〉2, which corrects for unresolved fluctuations in gas density n on scales below the grid-spacing of coarse-grained simulations. We investigate in detail the impact of this inhomogeneous subgrid clumping on reionization and its observables, as follows: (1) Previous attempts generally underestimated the clumping factor because of insufficient mass resolution. We perform a high-resolution N-body simulation that resolves haloes down to the pre-reionization Jeans mass to derive the time-dependent, spatially varying local clumping factor and a fitting formula for its correlation with local overdensity. (2) We then perform a large-scale N-body and radiative transfer simulation that accounts for this inhomogeneous subgrid clumping by applying this clumping factor-overdensity correlation. Boosting recombination significantly slows the expansion of ionized regions, which delays completion of reionization and suppresses 21 cm power spectra on large scales in the later stages of reionization. (3) We also consider a simplified prescription in which the globally averaged, time-evolving clumping factor from the same high-resolution N-body simulation is applied uniformly to all cells in the reionization simulation, instead. Observables computed with this model agree fairly well with those from the inhomogeneous clumping model, e.g. predicting 21 cm power spectra to within 20 per cent error, suggesting it may be a useful approximation.

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Large-scale motions in the adenylate kinase solution ensemble: Coarse-grained simulations and comparison with solution X-ray scattering

Chemical Physics ◽

10.1016/j.chemphys.2011.08.015 ◽

2012 ◽

Vol 396 ◽

pp. 84-91 ◽

Cited By ~ 19

Author(s):

Michael D. Daily ◽

Lee Makowski ◽

George N. Phillips ◽

Qiang Cui

Keyword(s):

Adenylate Kinase ◽

Large Scale ◽

Coarse Grained ◽

X Ray ◽

X Ray Scattering ◽

Coarse Grained Simulations ◽

Ray Scattering

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Coarse-grained simulation reveals key features of HIV-1 capsid self-assembly

10.1101/040741 ◽

2016 ◽

Cited By ~ 2

Author(s):

John M A Grime ◽

James F Dama ◽

Barbie K Ganser-Pornillos ◽

Cora L Woodward ◽

Grant J Jensen ◽

...

Keyword(s):

Self Assembly ◽

Coarse Grained ◽

Capsid Assembly ◽

Molecular Crowding ◽

Local Conditions ◽

Conformational Variability ◽

Multi Stage ◽

Capsid Shell ◽

Coarse Grained Simulations ◽

Hiv 1

The maturation of HIV-1 viral particles is essential for viral infectivity. During maturation, many copies of the capsid protein (CA) self-assemble into a capsid shell to enclose the viral RNA. The mechanistic details of the initiation and early stages of capsid assembly remain to be delineated. We present coarse-grained simulations of capsid assembly under various conditions, considering not only capsid lattice self-assembly but also the potential disassembly of capsid upon delivery to the cytoplasm of a target cell. The effects of CA concentration, molecular crowding, and the conformational variability of CA are described, with results indicating that capsid nucleation and growth is a multi-stage process requiring well-defined metastable intermediates. Generation of the mature capsid lattice is sensitive to local conditions, with relatively subtle changes in CA concentration and molecular crowding influencing self-assembly and the ensemble of structural morphologies.

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Trapping On-Pathway Intermediates for Large Scale Conformational Changes with Coarse-Grained Simulations

Biophysical Journal ◽

10.1016/j.bpj.2016.11.2625 ◽

2017 ◽

Vol 112 (3) ◽

pp. 485a

Author(s):

Laura Orellana ◽

Özge Yoluk ◽

Oliver Carrillo ◽

Modesto Orozco ◽

Erik Lindahl

Keyword(s):

Conformational Changes ◽

Large Scale ◽

Coarse Grained ◽

Coarse Grained Simulations

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Roles of Capsid-Interacting Host Factors in Multimodal Inhibition of HIV-1 by PF74

Journal of Virology ◽

10.1128/jvi.03116-15 ◽

2016 ◽

Vol 90 (12) ◽

pp. 5808-5823 ◽

Cited By ~ 40

Author(s):

Akatsuki Saito ◽

Damien Ferhadian ◽

Gregory A. Sowd ◽

Erik Serrao ◽

Jiong Shi ◽

...

Keyword(s):

Mechanism Of Action ◽

Dose Response ◽

Response Curve ◽

Cyclophilin A ◽

Dose Response Curve ◽

Host Factors ◽

Viral Capsid ◽

Antiviral Compound ◽

Drug Concentrations ◽

Hiv 1

ABSTRACTThe viral capsid of HIV-1 interacts with a number of host factors to orchestrate uncoating and regulate downstream events, such as reverse transcription, nuclear entry, and integration site targeting. PF-3450074 (PF74), an HIV-1 capsid-targeting low-molecular-weight antiviral compound, directly binds to the capsid (CA) protein at a site also utilized by host cell proteins CPSF6 and NUP153. Here, we found that the dose-response curve of PF74 is triphasic, consisting of a plateau and two inhibitory phases of different slope values, consistent with a bimodal mechanism of drug action. High PF74 concentrations yielded a steep curve with the highest slope value among different classes of known antiretrovirals, suggesting a dose-dependent, cooperative mechanism of action. CA interactions with both CPSF6 and cyclophilin A (CypA) were essential for the unique dose-response curve. A shift of the steep curve at lower drug concentrations upon blocking the CA-CypA interaction suggests a protective role for CypA against high concentrations of PF74. These findings, highlighting the unique characteristics of PF74, provide a model in which its multimodal mechanism of action of both noncooperative and cooperative inhibition by PF74 is regulated by interactions of cellular proteins with incoming viral capsids.IMPORTANCEPF74, a novel capsid-targeting antiviral against HIV-1, shares its binding site in the viral capsid protein (CA) with the host factors CPSF6 and NUP153. This work reveals that the dose-response curve of PF74 consists of two distinct inhibitory phases that are differentially regulated by CA-interacting host proteins. PF74's potency depended on these CA-binding factors at low doses. In contrast, the antiviral activity of high PF74 concentrations was attenuated by cyclophilin A. These observations provide novel insights into both the mechanism of action of PF74 and the roles of host factors during the early steps of HIV-1 infection.

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