CaverDock: a molecular docking-based tool to analyse ligand transport through protein tunnels and channels

Abstract

Motivation Protein tunnels and channels are key transport pathways that allow ligands to pass between proteins’ external and internal environments. These functionally important structural features warrant detailed attention. It is difficult to study the ligand binding and unbinding processes experimentally, while molecular dynamics simulations can be time-consuming and computationally demanding. Results CaverDock is a new software tool for analysing the ligand passage through the biomolecules. The method uses the optimized docking algorithm of AutoDock Vina for ligand placement docking and implements a parallel heuristic algorithm to search the space of possible trajectories. The duration of the simulations takes from minutes to a few hours. Here we describe the implementation of the method and demonstrate CaverDock’s usability by: (i) comparison of the results with other available tools, (ii) determination of the robustness with large ensembles of ligands and (iii) the analysis and comparison of the ligand trajectories in engineered tunnels. Thorough testing confirms that CaverDock is applicable for the fast analysis of ligand binding and unbinding in fundamental enzymology and protein engineering. Availability and implementation User guide and binaries for Ubuntu are freely available for non-commercial use at https://loschmidt.chemi.muni.cz/caverdock/. The web implementation is available at https://loschmidt.chemi.muni.cz/caverweb/. The source code is available upon request. Supplementary information Supplementary data are available at Bioinformatics online.

Dynamics, a Powerful Component of Current and Future in Silico Approaches for Protein Design and Engineering

“…In these studies, the tracking of ligands and water molecules with AQUA-DUCT helped to detected important features related to transport phenomena and to identify remote mutations governing the specificity and activity of these enzymes [84,85]. As an alternative to very costly explicit MD simulations, the passage of ligands through biomolecules can be explored by docking these ligands to an ensemble of precomputed molecular tunnels with CaverDock software [64,65] (Figure 3B). Benefiting from the fast operation of CaverDock calculation, it is possible to run the calculations over such an ensemble for multiple different ligands.…”

“…As an alternative to very costly explicit MD simulations, the passage of ligands through biomolecules can be explored by docking these ligands to an ensemble of precomputed molecular tunnels with CaverDock software [64,65] (Figure 3B). Benefiting from the fast operation of CaverDock calculation, it is possible to run the calculations over such an ensemble for multiple different ligands.…”

“…Such flexibility is capable of opening the narrowest sections of the investigated tunnels connected with the high-energy barriers, enabling the passage of various ligands via tunnels in cytochrome P450 17A1 and leukotriene A4 hydrolase/aminopeptidase [88]. Dealing with flexible residues during docking is more computationally demanding and should be used cautiously, as it can lead to the generation of the unrealistic conformation of flexible residues [65]. Marques et al benchmarked the capabilities of CaverDock for protein engineering against predictions from sophisticated metadynamics, adaptive sampling, and funnel-metadynamics techniques [89].…”

DockVis: Visual Analysis of Molecular Docking Trajectories

“…This kind of combined approach was used in the SLITHER [LKC*09], where the authors used the docking engine from AutoDockK4 [MHL*09] to quickly search possible positions of the ligand inside the protein along its unbinding pathway. Similarly, the very recently released tool, CaverDock [VFP*19, FVP*19, PVF*19], calculates the ligand passage by iterative molecular docking. It is using an optimized docking algorithm from AutoDock Vina [TO10] combined with the predefined geometry of access pathways from CAVER 3.02 [CPB*12].…”

“…CaverDock [VFP*19, FVP*19, PVF*19] simulates the transportation of a ligand through a tunnel using a stepwise algorithm. Firstly, the input spheres representing the tunnel are sliced into a sequence of discs (Figure 1).…”