Computational Modeling of the Virucidal Inhibition Mechanism for Broad-Spectrum Antiviral Nanoparticles and HPV16 Capsid Segments

Abstract

Solid core nanoparticles (NPs) coated with sulfonated ligands that mimic heparan sulfate proteoglycans (HSPGs) can exhibit virucidal activity against many viruses that utilize HSPG interactions with host cells for the initial stages of infection. How the interactions of these NPs with large capsid segments of HSPG-interacting viruses lead to their virucidal activity has been unclear. Here, we describe the interactions between sulfonated NPs and segments of the human papilloma virus type 16 (HPV16) capsids using atomistic molecular dynamics simulations. The simulations demonstrate that the NPs primarily bind at the interfaces of two HPV16 capsid proteins. After equilibration, the distances and angles between capsid proteins in the capsid segments are larger for the systems in which the NPs bind at the interfaces of capsid proteins. Over time, NP binding can lead to breaking of contacts between two neighboring proteins. The revealed mechanism of NPs targeting the interfaces between pairs of capsid proteins can be utilized for designing new generations of virucidal materials and contribute to the development of new broad-spectrum non-toxic virucidal materials.

Figure 1.. HPV16 virus capsid and its segments formed by L1 pentamer proteins.

a) Cryo-EM structure of the HPV16 capsid, assembled from L1 pentamer proteins (from Ref.). Labeled pentamers contribute to capsid segments examined in MD simulations. The largest segment examined, formed by four L1 pentamers, is marked by the cyan frame. The atoms are colored according to their radial distance from the capsid center. Pentamer labels (A, F, B, C) correspond to labels used in figures and analyses described below. b) Conformations of the capsid segment containing two L1 pentamers at the initial time and after 200 ns of MD simulations. The pentamers are colored in blue (A) and red (F), and the aqueous solution is not shown for clarity. c) Conformations of the same segment in the presence of the MUS:OT gold nanoparticle at the initial time (left) and after 200 ns of MD simulations (right), presented in the side and top views. Gold atoms, MUS ligands and OT ligands are shown in yellow, purple, and teal, respectively.

Figure 2.. Simulated systems of larger HPV16 capsid segments alone and interacting with sulfonated ligand-coated gold core nanoparticle.

a) Conformations of the capsid segment containing three L1 pentamers after 200 ns of MD simulations. b) Conformations of the three pentamer segment in the presence of the MUS:OT NP after 200 ns of MD simulations. c) Conformations of the capsid segment containing four L1 pentamers after 115 ns of MD simulations. b) Conformations of the four pentamer segment in the presence of the MUS:OT NP after 115 ns of MD simulations. The pentamers are colored in blue (A), red (F), green (B), and orange (C), and the aqueous solution is not shown for clarity. The color scheme of the NP is the same as in Figure 1.

Figure 3.. Distances and angles between pentamers in HPV capsid segments alone and when interacting with MUS:OT NP.

a) Representative snapshots of two-pentamer capsid segments with pentamers assuming different distances and angles with respect to each other. The snapshot times are labeled in the distance and angle plots in panels (b-c) below. b) Distance between A and F pentamers alone and when interacting with NP for two-pentamer segment systems. c) Angle between A and F pentamers alone and when interacting with NP for two-pentamer segment systems. d) Distance between A and F pentamers alone and when interacting with NP for three-pentamer segment systems. e) Angle between A and F pentamers alone and when interacting with NP for three-pentamer segment systems.

Figure 4.. Interactions of MUS:OT NP at the interface of two L1 pentamers in the two-pentamer system.

a) A snapshot of the NP interacting at the interface of two pentamers, shown in faded blue and red. The NP interacts with two distinct chains of both A and F pentamers, labeled as A1 (green), A5 (orange), F1 (purple) and F2 (black). The NP gold core is shown in yellow, and MUS and OT ligands are not shown for clarity. b) Side and top views of two chains of the pentamer typically found to interact with the NP, highlighted in red. The residues consistently found to interact with NP are shown by their Cα atoms (green, white, blue and red spheres label their residue types, namely polar, non-polar, basic and acidic) and labeled with residue indices. c) Contact maps of residues of the four chains of two-pentamer systems found to interact with NP over the course of the simulation. Colors in the contact maps match the colors of the four chains labeled within pentamers in panel a (A5 – orange, F2 – black, A1 – green, and F1 – purple). White regions in contact maps denote no contact.

Figure 5.. Contact maps of L1 pentamer interactions in two-pentamer segments alone and when interacting with MUS:OT NP.

a-d) Contact maps of A1 and A5 chain residues in contact with F pentamer and F1 and F2 chain residues in contact with A pentamer within two-pentamer systems over the course of the simulation. e-h) Contact maps of A1 and A5 chain residues in contact with F pentamer and F1 and F2 chain residues in contact with A pentamer within two-pentamer systems in the presence of MUS:OT NP over the course of the simulation. The colors in the contact maps match the colors of the four chains within pentamers shown in Figure 4a. White regions in the contact maps denote no contact.

Figure 6.. A scheme of MUS:OT NP effect on HPV16 capsid segments.

MUS:OT NPs (2.4 nm gold cores) bind to interfaces of two L1 proteins and wedge in between them. The NPs eventually lead to loss of contacts between L1 proteins at this interface.