Comparative Normal Mode Analysis of the Dynamics of DENV and ZIKV Capsids

Hsieh, Yin-Chen; Poitevin, Frédéric; Delarue, Marc; Koehl, Patrice

doi:10.3389/fmolb.2016.00085

Cited by 14 publications

(12 citation statements)

References 88 publications

(134 reference statements)

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“…The functional mechanisms of a macromolecule are inferred by the structural dynamics of its constituent proteins. However, the investigation into the dynamics of such large complexes has been hindered by limitations in computational power (31,32). Earlier research has focused on the mechanical properties of viral capsids and invoked continuum modeling or coarse-graining to investigate the collapse of viral capsids under an applied force (33).…”

Section: Introductionmentioning

confidence: 99%

Unraveling the Motions behind Enterovirus 71 Uncoating

Ross

Atılgan

Bishop

et al. 2018

Biophysical Journal

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Enterovirus 71 can be a severe pathogen in small children and immunocompromised adults. Virus uncoating is a critical step in the infection of the host cell; however, the mechanisms that control this process remain poorly understood. We applied normal mode analysis and perturbation response scanning to several complexes of the virus capsid and present a coarse-graining approach to analyze the full capsid. We show that our method offers an alternative to expressing the system as a set of rigid blocks and accounts for the interconnection between nodes within each subunit and protein interfaces across the capsid. In our coarse-grained approach, the modes associated with capsid expansion are captured in the first three nondegenerate modes and correspond to the changes observed in structural studies of the virus. We show that the resolution of the analysis may be modified without losing information on the global motions leading to uncoating. Perturbation response scanning revealed that a protomer cannot serve as a functional unit to explain deformations of the capsid. Instead, we define a pentamer as the minimum functional unit to investigate changes within the capsid. From the modal analysis and perturbation response scanning, we locate a hotspot region surrounding the fivefold axis. The range of the effect of these single, hotspot residues extend to 140 Å. The perturbation of internal capsid residues in this region displayed greatest propensity to capsid expansion, thus indicating the significant role that the RNA genome may play in triggering uncoating.

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Section: Introductionmentioning

confidence: 99%

Unraveling the Motions behind Enterovirus 71 Uncoating

Ross

Atılgan

Bishop

et al. 2018

Biophysical Journal

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“…The atomic density n i (see Equation ( 37)) is itself a function of the σ k of the atoms k in the neighborhood of i, that is, a spherical region of size R c . The n i and σ i are then computed self-consistently using Equations (37) and (38), as described by Halle. 4 At convergence, the computed σ i are scaled such that their mean value over a protein is equal to the mean experimental AMSD over the same protein.…”

Section: 8 Inmentioning

confidence: 99%

“…Her observation has been confirmed multiple times since then. Coarse grained NMA based on the ENM have proved useful to characterize allosteric changes in conformation, such as the switch undergone by hemoglobin from its tense (T) form to its relaxed (R) form, 32 to analyze conformational transitions in DNA‐based poymerases, 33 to analyze global ribosome motions, 34 and to study the dynamics of viral capsids, 35–38 among others. Such coarse‐grained analyses of biomolecular dynamics have developed as a viable alternative to traditional molecular dynamics simulations 23,39–42 .…”

Section: Introductionmentioning

confidence: 99%

Parameterizing elastic network models to capture the dynamics of proteins

2021

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Coarse-grained normal mode analyses of protein dynamics rely on the idea that the geometry of a protein structure contains enough information for computing its fluctuations around its equilibrium conformation. This geometry is captured in the form of an elastic network (EN), namely a network of edges between its residues. The normal modes of a protein are then identified with the normal modes of its EN. Different approaches have been proposed to construct ENs, focusing on the choice of the edges that they are comprised of, and on their parameterizations by the force constants associated with those edges. Here we propose new tools to guide choices on these two facets of EN. We study first different geometric models for ENs. We compare cutoff-based ENs, whose edges have lengths that are smaller than a cutoff distance, with Delaunay-based ENs and find that the latter provide better representations of the geometry of protein structures. We then derive an analytical method for the parameterization of the EN such that its dynamics leads to atomic fluctuations that agree with experimental B-factors. To limit overfitting, we attach a parameter referred to as flexibility constant to each atom instead of to each edge in the EN. The parameterization is expressed as a non-linear optimization problem whose parameters describe both rigid-body and internal motions. We show that this parameterization leads to improved ENs, whose dynamics mimic MD simulations better than ENs with uniform force constants, and reduces the number of normal modes needed to reproduce functional conformational changes.

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“…Nevertheless, the method is widely practiced in order to analyze the collective motion of protein and DNA, even in recent literatures, a few of them being cited as Refs. [6][7][8][9][10][11]. A reason why the method is so popular is because there has not been a better method which is able to handle the large scale structural fluctuation of protein in water in atomic scale.…”

Section: Introductionmentioning

confidence: 99%

Perspective: Structural fluctuation of protein and Anfinsen’s thermodynamic hypothesis

Hirata

Sugita

Yoshida

et al. 2018

The Journal of Chemical Physics

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The thermodynamics hypothesis, casually referred to as “Anfinsen’s dogma,” is described theoretically in terms of a concept of the structural fluctuation of protein or the first moment (average structure) and the second moment (variance and covariance) of the structural distribution. The new theoretical concept views the unfolding and refolding processes of protein as a shift of the structural distribution induced by a thermodynamic perturbation, with the variance-covariance matrix varying. Based on the theoretical concept, a method to characterize the mechanism of folding (or unfolding) is proposed. The transition state, if any, between two stable states is interpreted as a gap in the distribution, which is created due to an extensive reorganization of hydrogen bonds among back-bone atoms of protein and with water molecules in the course of conformational change. Further perspective to applying the theory to the computer-aided drug design, and to the material science, is briefly discussed.

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Comparative Normal Mode Analysis of the Dynamics of DENV and ZIKV Capsids

Cited by 14 publications

References 88 publications

Unraveling the Motions behind Enterovirus 71 Uncoating

Unraveling the Motions behind Enterovirus 71 Uncoating

Parameterizing elastic network models to capture the dynamics of proteins

Perspective: Structural fluctuation of protein and Anfinsen’s thermodynamic hypothesis

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