Fig 1.
Interactive protein-ligand rebinding using iMD-VR.
The top panel shows a schematic of Narupa, the open-source multiperson iMD-VR framework used to carry out the studies described herein, showing two participants using handheld wireless controllers to manipulate a real-time MD simulation of neuraminidase and oseltamivir. More information on the Narupa setup is available in ref 15. The bottom panel shows a three-dimensional representation of the binding pockets of each of the three protein systems interactively undocked and redocked, each bound to a ligand. The trypsin graphic (A) highlights the network of hydrogen bond interactions from Asp189, Ser190, and Gly219 to benzamidine (based off PDB code 1S0R). The neuraminidase graphic (B) highlights the hydrogen bonds between oseltamivir and both the 150-loop and a positively-charged trio of arginine residues of neuraminidase (based off a mutated neuraminidase structure derived from PDB code 2QWK). The HIV-1 protease graphic (C) highlights the hydrogen bonds between the hydroxyl group of amprenavir with both Asp25A and the protonated form of Asp25B (based off PDB code 1HPV). For HIV-1 protease, the protein ‘flaps’ have been highlighted in purple.
Fig 2.
Summary of iMD-VR docking tasks.
The ligands that were interactively unbound and rebound in a series of user tests, two for each of the three systems: Trypsin (A), Neuraminidase (B), and HIV-1 Protease (C). For each protein system, we devised two docking tasks, a training phase (where a trace representation of the ligand in the bound pose was present to guide users as shown in supplementary videos A–C in S1 File), and a testing phase, where no trace atoms were shown. For the testing tasks, parts of the ligand which interact with key residues have been highlighted in lilac. For proteins A and B, where the testing task ligand differs from training, the shared scaffold between the two ligands is highlighted in green.
Fig 3.
Recovering binding poses of three protein-ligand systems using iMD-VR.
Left: Ligand RMSD of iMD-VR generated trajectories by experts (compared to starting coordinates): (A) trypsin and benzamidine, (B) neuraminidase and oseltamivir, and (C) HIV-1 protease and amprenavir. For neuraminidase, the RMSD of the 150-loop residues is shown in blue. For HIV-1 protease, the RMSD of the active site flaps backbone atoms is shown in blue. Right: The top two (left plots) and top three (right plots) principal components (PC1-3) for representative trajectories of the three protein-ligand systems. Time is represented for each trajectory by the colour of the plot, starting at purple for the beginning of the trajectory and yellow for the end, passing through blue and green in between.
Fig 4.
Ligand RMSD over 200 nanoseconds of molecular dynamics.
Showing the RMSD of each of the three ligands (compared to the initial solvated, minimized and equilibrated bound coordinates) during 200 nanoseconds of molecular dynamics simulation. From top to bottom: (A) benzamidine (in trypsin), (B) oseltamivir (in neuraminidase), and (C) amprenavir in HIV-1 protease.
Fig 5.
Snapshots along the interactive unbinding and rebinding of amprenavir into HIV-1 protease.
The image in the upper left shows the bound “start” pose. (a)–(c) shown snapshots as the user unbinds amprenavir; (d) shows the unbound pose; and (e)–(g) shows snapshots as the user rebinds amprenavir. The corresponding RMSD time traces are shown in the middle plot, identical to that shown in Fig 3c.
Fig 6.
Minimum RMSD values for novice tasks.
(Left) Showing the minimum achieved RMSD of each small ligand novices tried to dock, where each participant is assigned a unique colour. Two ligands were docked for each system, in both ‘training’ and ‘testing’ phases; each ligand is denoted in Fig 2. To determine the extent to which user-identified poses aligned with the native RMSD, a non-interactive Narupa simulation was run for 50 picoseconds in the bound pose and the average RMSD (plus or minus two standard deviations) was calculated, shown as the purple box. The whiskers at the top of each box span 1 Angstrom. (Right) The pose corresponding to the minimum RMSD value shown is on the left for each participant, overlaid on top of one another. Testing tasks for the three are shown in the top row, training tasks are shown on the bottom.