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. 2017 Jul 19:8:15959.
doi: 10.1038/ncomms15959.

Physical properties of the HIV-1 capsid from all-atom molecular dynamics simulations

Juan R Perilla  1   2 , Klaus Schulten  1
Affiliations

Physical properties of the HIV-1 capsid from all-atom molecular dynamics simulations

Juan R Perilla et al. Nat Commun. .

Abstract

Human immunodeficiency virus type 1 (HIV-1) infection is highly dependent on its capsid. The capsid is a large container, made of ∼1,300 proteins with altogether 4 million atoms. Although the capsid proteins are all identical, they nevertheless arrange themselves into a largely asymmetric structure made of hexamers and pentamers. The large number of degrees of freedom and lack of symmetry pose a challenge to studying the chemical details of the HIV capsid. Simulations of over 64 million atoms for over 1 μs allow us to conduct a comprehensive study of the chemical-physical properties of an empty HIV-1 capsid, including its electrostatics, vibrational and acoustic properties, and the effects of solvent (ions and water) on the capsid. The simulations reveal critical details about the capsid with implications to biological function.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. The HIV-1 capsid.
(a) The HIV-1 capsid is made of a single capsid protein (CA), containing 11 α-helices and a 310 helix. (b) CA arranges into a fullerenic cone, consisting of pentamers (green) and hexamers (tan). The fully solvated HIV-1 capsid model without genome, including neutralizing ions and 150 mM NaCl, contains a total of 64,423,983 atoms.
Figure 2
Figure 2. Stability of the HIV-1 capsid.
(a) Time evolution of the root mean squared deviation (r.m.s.d.) for hexamers and pentamers, and the moving average with a window size of 10 ns is shown in blue. (b) For all area and height calculations, the three principal moments of inertia of the entire capsid define the x, y and z axes. The cross-sectional area is estimated as the area of an ellipse where the major and minor axes are the maximal distance between parts of the capsid along the [Image: see text] and [Image: see text] axes. The height of the capsid is defined as the longest distance from the tip (bottom) to the base (top) along the [Image: see text] axis. (c) Time evolution of the capsid’s cross-section, and the moving average with a 10 ns window size is shown in blue. (d) Time evolution of the height of the HIV-1 capsid; the moving average with a 10 ns window size is shown in blue.
Figure 3
Figure 3. Electrostatic potential averaged over the final 400 ns of the HIV-1 capsid simulation.
The electrostatic calculation includes all capsid atoms and all solvent molecules for a total of 64,423,983 atoms. The bar scale indicates the magnitude of the electrostatic potential in Volt, ranging from −1.3 V (red) to 6.0 V (blue). (a) Exterior view of the HIV-1 electrostatic potential. The red line indicates the location of the cross-section shown in b. (b) Cross-section of the electrostatic potential of the HIV-1 capsid. The bulk in the interior and exterior of the capsid assume the same electrostatic potential values, namely −1.3 V. (c) Electrostatics of the N-terminal domain of CA. The cypA binding loop and α-helix 4 (Fig. 1a) show a significant potential difference to the inner core of the capsid in d.
Figure 4
Figure 4. Gibbs free energy of the binding of sodium and chloride ions to CA hexamers and pentamers.
Free-energy isosurfaces at ΔG=−1.0 kcal mol−1. Sodium is represented in yellow and chloride in blue. (a) Binding of sodium and chloride to CA hexamers. The free energies were calculated over a total sampling time of 74.4 μs. (b) Binding of sodium and chloride to CA pentamers. The free energies were calculated over a total sampling time of 4.8 μs. (c) Distribution of ions on the entire HIV-1 capsid. A layer of chloride ions can be observed at the interior of the capsid, while sodium binds preferentially to the exterior of the capsid.
Figure 5
Figure 5. Acoustic properties of the HIV-1 capsid during the last 400 ns of simulations.
(a) Structural fluctuations of the capsid observed between two states separated 400 ns apart, ranging from −3 to +3 Å (red to blue). (b) Periodograms of the time series of the capsid motions. Four classes of periodograms were found: the two largest classes (N=10,743 and N=11,898) are dominated by the two lower fundamental frequencies (2.38 and 4.76 MHz); conversely, the two smallest classes (N=4,679 and N=2,786) are dominated by two higher fundamental frequencies (7.14 and 11.9 MHz). The medoids of each class are represented in red dots in b. The s.d. within each class is represented in blue error bars. (c) Projection of the periodogram clusters onto the structure of the capsid indicating the location of each cluster. (d) Top (base) and bottom (tip) view of the capsid coloured by the periodogram clusters. The four clusters are coloured orange, green, cyan and dark blue, respectively.
Figure 6
Figure 6. Mechanical motions of the HIV-1 capsid.
Collective motions were measured using principal component analysis over the last 400 ns of the capsid trajectory. (a) Cumulative contribution to variance from all the principal components. Inset: cumulative contribution to variance from the first 100 principal components. (b) Collectiveness of the first 800 principal components according to their participation number. (c,d) Projection of the displacement patterns for the first principal component, the direction of the displacement is represented by the direction of the arrow; similarly, the magnitude of the displacement is represented by the length of the arrow. Locations of pentamers are highlighted in green.
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