Molecular dynamics of the viral life cycle: progress and prospects

Jones, Peter Eugene; Pérez-Segura, Carolina; Bryer, Alexander J.; Perilla, Juan R.; Hadden‐Perilla, Jodi A.

doi:10.1016/j.coviro.2021.08.003

Cited by 28 publications

(14 citation statements)

References 98 publications

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“…Mean first-passage times can be predicted from theory in surprisingly complex geometries (56), but for the immature lattice, the problem was intractable without using simulation data due to the ability of Gag-Pol to rebind or 'stick' back onto the lattice through multiple contacts before successful dimerization encounters. More generally, modeling stages of viral assembly has been critical for establishing the regimes of energetic and kinetic parameters that distinguish successful assembly from malformed or kinetically trapped intermediates, such as in viral capsid assembly (57)(58)(59)(60). Computational models of self-assembly can be used to assess how additional complexity encountered in vivo, such as macromolecular co-factors (30,31,61), crowding (59,62), and changes to membrane-to-surface geometry (24), could help to promote or suppress assembly relative to in vitro conditions.…”

Section: Biochemical Measurements Of Gag Mobility In Vlps Agree With ...mentioning

confidence: 99%

Defects in the HIV immature lattice support essential lattice remodeling within budded virions

Guo

Saha

Saffarian

et al. 2022

Preprint

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For HIV virions to become infectious, the immature lattice of Gag polyproteins attached to the virion membrane must be cleaved. Cleavage cannot initiate without the protease formed by the homo-dimerization of domains linked to Gag. However, only 5% of the Gag polyproteins, termed Gag-Pol, carry this protease domain, and they are embedded within the structured lattice. The mechanism of Gag-Pol dimerization is unknown. Here, we use reaction-diffusion simulations of the immature Gag lattice as derived from experimental structures, showing that dynamics of the lattice on the membrane is unavoidable due to the missing 1/3 of the spherical protein coat. These dynamics allow for Gag-Pol molecules carrying the protease domains to detach and reattach at new places within the lattice. Surprisingly, dimerization timescales of minutes or less are achievable for realistic binding energies and rates despite retaining most of the large-scale lattice structure. We derive a formula allowing extrapolation of timescales as a function of interaction free energy and binding rate, thus predicting how additional stabilization of the lattice would impact dimerization times. We further show that during assembly, dimerization of Gag-Pol occurs stochastically and therefore must be actively suppressed to prevent early activation. By direct comparison to recent biochemical measurements within budded virions, we find that only moderately stable hexamer contacts (-12kBT<∆G<-8kBT) retain both the dynamics and lattice structures that are consistent with experiment. These dynamics are likely essential for proper maturation, and our models quantify and predict lattice dynamics and protease dimerization timescales that define a key step in understanding formation of infectious viruses.

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Section: Biochemical Measurements Of Gag Mobility In Vlps Agree With ...mentioning

confidence: 99%

Defects in the HIV immature lattice support essential lattice remodeling within budded virions

Guo

Saha

Saffarian

et al. 2022

Preprint

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“…All-atom molecular dynamics (MD) simulations are routinely used to probe protein-ligand and protein-protein interactions ( 28 – 30, 32 – 34 ). Molecular mechanics (MM) force fields (FF) are essential to MD simulations, and the reliability of the simulations depends heavily on the accuracy of the MM parameters adopted ( 35 ).…”

Section: Resultsmentioning

confidence: 99%

Equilibrium dynamics of the pre- and post-cleavage regions of SP1 are separately shifted by the HIV-1 maturation inhibitor Bevirimat

Perilla

2022

Preprint

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Human immunodeficiency virus type 1 (HIV-1) assembly and maturation proceeds in two distinct steps. During assembly, viral Gag oligomerizes into a hexagonal polyprotein lattice incorporating the capsid protein (CA) and spacer peptide 1 (SP1) domains, that constitute the immature Gag lattice. During maturation, CTD-SP1 hexamers formed in the previous step are cleaved by HIV-1 protease, causing a dramatic rearrangement of the immature virion to its mature, infectious form. The first-generation maturation inhibitor (MI) bevirimat (BVM) is reported to block the final cleavage between CA and SP1, thus blocking HIV maturation. In contrast, the host factor inositol hexakisphosphate (IP6) is a co-factor of Gag assembly and facilitates the formation of a quaternary arrangement of SP1 known as the six helix bundle (6HB). Here, starting from a MAS NMR structure and using atomistic free energy calculations, we establish that binding of BVM and IP6 to the immature lattice lacks any cooperativity or avidity. Furthermore, we rationalize the molecular origin of HIV resistance to BVM by determining the role of BVM on the stability of the 6HB and by revealing that SP1 shows independent dynamics for its pre- and post-cleavage regions. Finally, results from our simulations permit us to propose a novel chemical scaffold for the design of maturation inhibitors based on BVM and IP6.

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“…Viruses are particularly highly packed systems, due to limitations of their genome size, and therefore, a viral capsid must be dynamic to perform many processes (e.g., assembly, attachment, and entry to the host cell) 9 . Hence many molecular dynamics (MD) studies have been carried out on virus capsids and VLPs at the all‐atom and coarse‐grained levels 10–13 . For example, all‐atom simulations of a complete satellite tobacco mosaic virus (9540 amino‐acid residues) in explicit water for over 50 ns demonstrated the stability of the entire virion 14 .…”

Section: Introductionmentioning

confidence: 99%

Long‐time scale simulations of virus‐like particles from three human‐norovirus strains

et al. 2023

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The dynamics of the virus like particles (VLPs) corresponding to the GII.4 Houston, GII.2 SMV, and GI.1 Norwalk strains of human noroviruses (HuNoV) that cause gastroenteritis was investigated by means of long-time (about 30 μs in the laboratory timescale) molecular dynamics simulations with the coarse-grained UNRES force field.The main motion of VLP units turned out to be the bending at the junction between the P1 subdomain (that sits in the VLP shell) and the P2 subdomain (that protrudes outside) of the major VP1 protein, this resulting in a correlated wagging motion of the P2 subdomains with respect to the VLP surface. The fluctuations of the P2 subdomain were found to be more pronounced and the P2 domain made a greater angle with the normal to the VLP surface for the GII.2 strain, which could explain the inability of this strain to bind the histo-blood group antigens (HBGAs).

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Molecular dynamics of the viral life cycle: progress and prospects

Cited by 28 publications

References 98 publications

Defects in the HIV immature lattice support essential lattice remodeling within budded virions

Defects in the HIV immature lattice support essential lattice remodeling within budded virions

Equilibrium dynamics of the pre- and post-cleavage regions of SP1 are separately shifted by the HIV-1 maturation inhibitor Bevirimat

Long‐time scale simulations of virus‐like particles from three human‐norovirus strains

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