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Simulations reveal that the HIV-1 gp120-CD4 complex dissociates via complex pathways and is a potential target of the polyamidoamine (PAMAM) dendrimer
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10.1063/1.4812801
/content/aip/journal/jcp/139/2/10.1063/1.4812801
http://aip.metastore.ingenta.com/content/aip/journal/jcp/139/2/10.1063/1.4812801

Figures

Image of FIG. 1.
FIG. 1.

SMD simulations of the dissociation of the gp120-CD4 complex. (a) The simulation system comprising gp120 (red), CD4 (blue), Cl ions (yellow), and water molecules (cyan background). (b) Force versus extension curves for different pulling velocities. (c) Snapshots of the initial structure, the structure at bond rupture (separation 9.4 Å), and well after bond rupture (separation 22.7 Å) for ν = 0.0021 Å/ps.

Image of FIG. 2.
FIG. 2.

Force versus extension profiles (green) of the gp120-CD4 complex for three different pulling velocities with the initial structure following 19 ns of MD simulation.Running averages were computed with appropriate block sizes for each pulling velocity (blue line). The region approaching rupture (red line) was fit using a straight line (black line). The slope of this straight line multiplied by the pulling velocity gave the loading rate (pN/ps) at rupture. The maximum of the running average of the force (blue) gave the rupture force.

Image of FIG. 3.
FIG. 3.

Dissociation pathways of the gp120-CD4 complex. (a) Two regimes of the dependence of on with initial configurations obtained after 1 ns (black line) and 19 ns (red line) of MD and the corresponding dependence of on (inset). Error bars are standard deviations obtained from four different realizations of our simulations at each pulling velocity. Time-evolution of (b) the number of contacts and (c) the binding energy for four pulling velocities, two each in the large (cyan and green) and the small (purple and blue) regimes. Snapshots indicating new contacts formed by residues Asn 280 and Ala 281 in the small regime (ν = 0.0034 Å/ps) (e) but not in the high regime (ν = 0.034 Å/ps) (d). Note that an inter-atomic separation of 3 Å or less indicates a contact.

Image of FIG. 4.
FIG. 4.

SMD simulations of the gp120-CD4 complex dissociation in the presence of PAMAM. (a) The simulation system comprising gp120 (red), CD4 (blue), PAMAM (green), Cl ions (yellow), and water molecules (not shown). (b) Force versus extension curves for different pulling velocities. (c) Snapshots of the initial structure, the structure at bond rupture (separation 6.6 Å), and well after bond rupture (separation 23.8 Å) for ν = 0.0068 Å/ps.

Image of FIG. 5.
FIG. 5.

Dissociation pathways of the gp120-CD4 complex in the presence of PAMAM. (a) The dependence of on ν and (inset) with PAMAM (blue line) compared with that without PAMAM (black and red lines; see Fig. 1 ). Error bars are standard deviations from four realizations of our simulations at each ν. Time-evolution of (b) the number of contacts and (c) the binding energy for four pulling velocities, two each in the large (cyan and green) and the small (purple and blue) regimes. Snapshots indicating new contacts formed by the residue Cys 126 in the small regime (ν = 0.0033 Å/ps) (e) but not in the high regime (ν = 0.033 Å/ps) (d). Note that an inter-atomic separation of 3 Å or less indicates a contact.

Image of FIG. 6.
FIG. 6.

Hydration of the hydrophobic cavity of gp120. The hydrophobic cavity of gp120, in the middle of the green region surrounding the Phe 43 residue of CD4 (yellow) contains more water molecules (red and white) in the absence of PAMAM (a) than in the presence of PAMAM (b).

Tables

Generic image for table
Table I.

Inter-atomic contacts between gp120 and CD4 influenced by PAMAM. The number of inter-atomic contacts between gp120 residues and CD4 in the low and high loading rate regimes in the absence and presence of PAMAM, determined at a separation of ∼1.8 Å during pulling. The Kyte-Doolittle hydrophobicity index of the residues is mentioned, where positive values indicate hydrophobicity and negative values indicate hydrophilicity. The detailed lists of atomic contacts are in Tables S1 and S2.

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/content/aip/journal/jcp/139/2/10.1063/1.4812801
2013-07-12
2014-04-25
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752b84549af89a08dbdd7fdb8b9568b5 journal.articlezxybnytfddd
Scitation: Simulations reveal that the HIV-1 gp120-CD4 complex dissociates via complex pathways and is a potential target of the polyamidoamine (PAMAM) dendrimer
http://aip.metastore.ingenta.com/content/aip/journal/jcp/139/2/10.1063/1.4812801
10.1063/1.4812801
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