HIV Capsid Assembly, Mechanism, and Structure

Chen, Bin

doi:10.1021/acs.biochem.6b00159

Cited by 37 publications

(39 citation statements)

References 145 publications

(452 reference statements)

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“…Fig 7(C) and 7(F) show the structure of a pentamer in the top and front views, respectively. In HIV-1 capsid structure, the positions of pentamers determine the shape of the assembly and 12 pentamers are needed to form a closed cone [ 38 ]. In Fig 7(B)–7(F) , all N-terminal domains are colored red.…”

Section: Resultsmentioning

confidence: 99%

“…Structural studies show that pentamers incur sharp curvatures while forming hemispherical ends of the capsule-shaped HIV-1 capsid surface [ 38 , 39 ]. However, the dynamic role of the pentamers has not been thoroughly examined.…”

Section: Resultsmentioning

confidence: 99%

“…Our result indicates that while the structural role of pentamers is forming both hemispherical ends of the capsule-shaped HIV-1 capsid shell [ 38 , 39 ], the dynamic role of pentamers is to stabilize both ends of the capsid by suppressing their fluctuations. Our result is in agreement with the idea that capsid disassembly should start when the pentamers become destabilized [ 40 ].…”

Section: Resultsmentioning

confidence: 99%

“…Second, we identify the dynamic role of the twelve pentamers on the capsid. While the structural role of the pentamers was thought to form the hemispherical ends of the capsule-shaped HIV-1 capsid [ 38 , 39 ], analysis of the first group of modes and the associated global fluctuations reveal what the dynamic role of the pentamers is: pentamers serve to stabilize both ends of the capsid dynamically by suppressing the fluctuation dynamics of the capsid at around their locations. This is consistent with the results obtained from MD simulation [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

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All-atom normal mode dynamics of HIV-1 capsid

Song

2018

PLoS Comput Biol

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Dynamics of biomolecular assemblies offer invaluable insights into their functional mechanisms. For extremely large biomolecular systems, such as HIV-1 capsid that has nearly 5 millions atoms, obtaining its normal mode dynamics using even coarse-grained models can be a challenging task. In this work, we have successfully carried out a normal mode analysis of an entire HIV-1 capsid in full all-atom details. This is made possible through our newly developed BOSE (Block of Selected Elasticity) model that is founded on the principle of resonance discovered in our recent work. The resonance principle makes it possible to most efficiently compute the vibrations of a whole capsid at any given frequency by projecting the motions of component capsomeres into a narrow subspace. We have conducted also assessments of the quality of the BOSE modes by comparing them with benchmark modes obtained directly from the original Hessian matrix. Our all-atom normal mode dynamics study of the HIV-1 capsid reveals the dynamic role of the pentamers in stabilizing the capsid structure and is in agreement with experimental findings that suggest capsid disassembly and uncoating start when the pentamers become destabilized. Our results on the dynamics of hexamer pores suggest that nucleotide transport should take place mostly at hexamers near pentamers, especially at the larger hemispherical end.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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All-atom normal mode dynamics of HIV-1 capsid

Song

2018

PLoS Comput Biol

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“…In the maturing HIV virion, the growing CA lattice folds in the third dimension and condenses around the nucleoprotein complex containing the viral genome (48,49), to yield a truncated cone-shaped capsid containing a fraction (1000-1500 copies) of the available CA subunits in the virion (49,50). Closure and shape are the result of the introduction of CA pentamer ''defects'' at defined positions in the hexagonal lattice (49,50). In vitro, both open hollow tubes without pentagonal defects, coneshaped capsid-like particles (51)(52)(53)(54)(55), and sheets (46,47) may be formed.…”

Section: Introductionmentioning

confidence: 99%

Kinetics of Surface-Driven Self-Assembly and Fatigue-Induced Disassembly of a Virus-Based Nanocoating

Valbuena

Mateu

2017

Biophysical Journal

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Self-assembling protein layers provide a ''bottom-up'' approach for precisely organizing functional elements at the nanoscale over a large solid surface area. The design of protein sheets with architecture and physical properties suitable for nanotechnological applications may be greatly facilitated by a thorough understanding of the principles that underlie their self-assembly and disassembly. In a previous study, the hexagonal lattice formed by the capsid protein (CA) of human immunodeficiency virus (HIV) was self-assembled as a monomolecular layer directly onto a solid substrate, and its mechanical properties and dynamics at equilibrium were analyzed by atomic force microscopy. Here, we use atomic force microscopy to analyze the kinetics of self-assembly of the planar CA lattice on a substrate and of its disassembly, either spontaneous or induced by materials fatigue. Both selfassembly and disassembly of the CA layer are cooperative reactions that proceed until a phase equilibrium is reached. Self-assembly requires a critical protein concentration and is initiated by formation of nucleation points on the substrate, followed by lattice growth and eventual merging of CA patches into a continuous monolayer. Disassembly of the CA layer showed hysteresis and appears to proceed only after large enough defects (nucleation points) are formed in the lattice, whose number is largely increased by inducing materials fatigue that depends on mechanical load and its frequency. Implications of the kinetic results obtained for a better understanding of self-assembly and disassembly of the HIV capsid and protein-based two-dimensional nanomaterials and the design of anti-HIV drugs targeting (dis)assembly and biocompatible nanocoatings are discussed.

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Discovery of novel 1,2,4‐triazole phenylalanine derivatives targeting an unexplored region within the interprotomer pocket of the HIV capsid protein

Jiang

Sharma

Rathi

et al. 2022

Journal of Medical Virology

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Human immunodeficiency virus (HIV) capsid (CA) protein is a promising target for developing novel anti‐HIV drugs. Starting from highly anticipated CA inhibitors PF‐74, we used scaffold hopping strategy to design a series of novel 1,2,4‐triazole phenylalanine derivatives by targeting an unexplored region composed of residues 106–109 in HIV‐1 CA hexamer. Compound d19 displayed excellent antiretroviral potency against HIV‐1 and HIV‐2 strains with EC50 values of 0.59 and 2.69 µM, respectively. Additionally, we show via surface plasmon resonance (SPR) spectrometry that d19 preferentially interacts with the hexameric form of CA, with a significantly improved hexamer/monomer specificity ratio (ratio = 59) than PF‐74 (ratio = 21). Moreover, we show via SPR that d19 competes with CPSF‐6 for binding to CA hexamers with IC50 value of 33.4 nM. Like PF‐74, d19 inhibits the replication of HIV‐1 NL4.3 pseudo typed virus in both early and late stages. In addition, molecular docking and molecular dynamics simulations provide binding mode information of d19 to HIV‐1 CA and rationale for improved affinity and potency over PF‐74. Overall, the lead compound d19 displays a distinct chemotype form PF‐74, improved CA affinity, and anti‐HIV potency.

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HIV Capsid Assembly, Mechanism, and Structure

Cited by 37 publications

References 145 publications

All-atom normal mode dynamics of HIV-1 capsid

All-atom normal mode dynamics of HIV-1 capsid

Kinetics of Surface-Driven Self-Assembly and Fatigue-Induced Disassembly of a Virus-Based Nanocoating

Discovery of novel 1,2,4‐triazole phenylalanine derivatives targeting an unexplored region within the interprotomer pocket of the HIV capsid protein

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