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. 2016 Dec 27;3:85.
doi: 10.3389/fmolb.2016.00085. eCollection 2016.

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

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Free PMC article

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

Yin-Chen Hsieh et al. Front Mol Biosci. .
Free PMC article

Abstract

Key steps in the life cycle of a virus, such as the fusion event as the virus infects a host cell and its maturation process, relate to an intricate interplay between the structure and the dynamics of its constituent proteins, especially those that define its capsid, much akin to an envelope that protects its genomic material. We present a comprehensive, comparative analysis of such interplay for the capsids of two viruses from the flaviviridae family, Dengue (DENV) and Zika (ZIKV). We use for that purpose our own software suite, DD-NMA, which is based on normal mode analysis. We describe the elements of DD-NMA that are relevant to the analysis of large systems, such as virus capsids. In particular, we introduce our implementation of simplified elastic networks and justify their parametrization. Using DD-NMA, we illustrate the importance of packing interactions within the virus capsids on the dynamics of the E proteins of DENV and ZIKV. We identify differences between the computed atomic fluctuations of the E proteins in DENV and ZIKV and relate those differences to changes observed in their high resolution structures. We conclude with a discussion on additional analyses that are needed to fully characterize the dynamics of the two viruses.

Keywords: Dengue; Zika; elastic network models; normal modes; proteins; viruses.

Figures

Figure 1
Figure 1
The capsid of ZIKV. (A) Cartoon representation of the capsid of ZIKV (PDB file 5IZ7). The capsid includes 180 copies of protein E. The three E proteins from each asymmetric unit are colored green, orange, and blue. (B) The elastic network of the capsid of ZIKV, constructed from the Cα only, with a cutoff Rc = 14 Å. (C) Inside view of the elastic network, obtained by cutting the full elastic network along the plane shown as a line on (B). Note that it is possible to identify rafts, as illustrated with one raft being contoured with a dashed rectangle (see text for details). All three panels were generated using Pymol (http://www.pymol.org).
Figure 2
Figure 2
Comparing the low frequencies of the normal modes of DENV and ZIKA. The frequencies of the first hundred normal modes of DENV (red circle, o) and ZIKV (blue cross, x) are plotted against the normal mode index (#), for the E protein by itself (left), for a raft (middle), and for the full capsid (right). The frequencies are in arbitrary units, as the force constants are also in arbitrary units. Note the decrease in the amplitude of those frequencies as the size of the complex increases. The insert in the right panel shows an enlargement for the first 50 normal modes; it highlights the degeneracy of the normal modes for a full capsid.
Figure 3
Figure 3
Correlated motions in the DENV E protein. Cross Correlation Matrices (CCM) obtained from the 94 first non-zero modes for the E protein alone (MONO, A), the E protein in the asymmetric unit (UNIT, B), and the E protein in the whole capsid (FULL, C). Those plot show correlations between the motions of Cα atoms in each complex considered. Both axes of a matrix are the amino acid residue index. Each cell in a matrix shows the correlation between the motions of two residues (Cα atoms) in the protein on a range from −1 (anticorrelated, blue) to 1 (correlated, red), with 0 conferring no correlation. (D) The E protein is shown in cartoon mode. The color code for the structure in (C) as well as for the X and Y axes of the CCM plots in (A) to follows the standard designation of the E protein domains I (red), II (yellow), and III (blue). The transmembrane domain is shown in purple. Panel (D) was generated using Pymol.
Figure 4
Figure 4
Correlated motions in the ZIKV E protein. Cross Correlation Matrices (CCM) obtained from the 94 first non-zero modes for the E protein alone (MONO, A), the E protein in the asymmetric unit (UNIT, B), and the E protein in the whole capsid (FULL, C). (D) The E protein is shown in cartoon mode. Colors and layout follow the same schemes as in Figure 3.
Figure 5
Figure 5
Correlated motions in the a E protein raft. Cross Correlation Matrices (CCM) obtained from the 94 first non-zero modes for a E protein raft alone (UNIT), and a raft in the whole capsid (FULL) for DENV (A,C), and for ZIKV (B,D). X axes and Y axes are residue indices. The positions of the six E proteins are marked, with labels and color codes defined on the structure in (E). (E) Cartoon model for the raft. Note that a raft includes two asymmetric units, labeled Unit A and Unit B. The first E protein of each unit, E1A and E1B form a dimer. Panel (E) was generated using Pymol.
Figure 6
Figure 6
Atomic fluctuations in the DENV and ZIKV E proteins. The atomic displacement fluctuations obtained from the 94 first non-zero modes for the E protein alone (MONO, A,B), the E protein in the asymmetric unit (UNIT, C,D), and the E protein in the whole capsid (FULL, E,F) are plotted as a function of the residue number for both DENV (PDB file 4CCT) and ZIKV (PDB file 5IZ7). The Y axis represents normalized displacements (see text for details). The color code follows the standard designation of the E protein domains for domains I (red) and III (blue), while domain II has been colored green to enhance visibility.
Figure 7
Figure 7
Comparison of normalized experimental and computed atomic fluctuations in the DENV and ZIKV E proteins. The computed atomic displacement fluctuations were obtained from the 94 first non-zero modes of the whole capsid shell. The experimental fluctuations are taken from the cryo-EM structures of DENV (4CCT, Kostyuchenko et al., 2013) and ZIKV (5IZ7, Kostyuchenko et al., 2016) The color code for the computed atomic fluctuation is: E protein domain I, red, II, green, III, blue, and transmembrane domain, purple.
Figure 8
Figure 8
Running time for DDNMA. The running time of the normal mode computation is plotted against the initial number of atoms (A), and the initial number of edges in the corresponding elastic network, EN (B). The timings are computed on a single Intel Core I7 processor running at 4.0 GHz with 8 GB of RAM.

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