Disclaimer

The following text complements the displayed results and adds more information about the data presented on the result page of each studied case.

CaverDock

The binary files and main features of the CaverDock program are described here:
https://loschmidt.chemi.muni.cz/caverdock/
https://www.fi.muni.cz/~xfilipov/caverdock/manual.pdf
https://academic.oup.com/bioinformatics/advance-article/doi/10.1093/bioinformatics/btz386/5488163
https://ieeexplore.ieee.org/document/8674575

In short, CaverDock1,2 simulates the transport process of the ligand through protein tunnels. The main workhorse is an iterative docking algorithm based on the well established software tools CAVER3 and AutoDock Vina4. In each step of the trajectory, the so called “drag atom” is constrained to the center point of the tunnel slice. The drag atom is specified in the settings and gives the direction to the moving ligand along the protein tunnel. The results of CaverDock are summarized by a lower-bound and a upper-bound ligand trajectory. The lower-bound trajectory is non-continuous, calculated using iterative docking, allowing the ligand to flip and move freely in each step. The upper-bound trajectory is smooth and continuous, calculated using iterative docking and heuristic trajectory search algorithm, due to smooth movement of the ligand without any jumps or flips.

Calculations

The CaverDock calculations for the Substrate and Inhibitor Dataset were carried out in four rounds. The first round was the classical CaverDock calculation, which treats the protein as a rigid body. Then we introduced sidechain flexibility in three iterations by adding two flexible bottleneck residues in each iteration.

Analysed CaverDock energies


Figure: Example energy profile from the CaverDock calculation. The binding energy (left vertical axis) is drawn as the full line. Tunnel radii (right vertical axis) is shown as the dotted line. The direction of the molecule in the plot is from the active site (marked by the star symbol) to the surface of the protein. Below the energy plot we show the corresponding tunnel calculated by CAVER 3.02.

Plots

The active site of the protein is situated at 0 in all of the generated plots. The plots were prepared in the original (unscaled) and scaled version. The scaled plots are scaled by binding energies from each trajectory for a given case. To display all of the scaled plots, click the “Summary of Scaled plots” button under the CaverDock result table.

Visualisation

Click the left mouse button in the browser window to control the JSmol scenes.
http://wiki.jmol.org/index.php/Mouse_Manual

The color scheme for the visualisation is:

References

  1. Vavra, O., Filipovic, J., Plhak, J., Bednar, D., Marques, S.M., Brezovsky, J., Stourac, J., Matyska, L., Damborsky, J., 2019: CaverDock: A Molecular Docking-Based Tool to Analyse Ligand Transport through Protein Tunnels and Channels. Bioinformatics, https://doi.org/10.1093/bioinformatics/btz386 Full text
  2. Filipovic, J., Vavra, O., Plhak, J., Bednar, D., Marques, S., Brezovsky, J., Matyska, L., Damborsky, J., 2019: CaverDock: A Novel Method for the Fast Analysis of Ligand Transport. IEEE/ACM Transactions on Computational Biology and Bioinformatics, DOI: 10.1109/TCBB.2019.2907492 Full text
  3. Chovancova, E., Pavelka, A., Benes, P., Strnad, O., Brezovsky, J., Kozlikova, B., Gora, A., Sustr, V., Klvana, M., Medek, P., Biedermannova, L., Sochor, J., Damborsky, J., 2012: CAVER 3.0: A Tool for Analysis of Transport Pathways in Dynamic Protein Structures. PLOS Computational Biology 8: e1002708. Full text
  4. Trott, O., Olson, A.J., 2010: AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization and Multithreading. Journal of Computational Chemistry 31: 455-461.