CAVER: a new tool to explore routes from protein clefts, pockets and cavities - PubMed (original) (raw)

CAVER: a new tool to explore routes from protein clefts, pockets and cavities

Martin Petrek et al. BMC Bioinformatics. 2006.

Abstract

Background: The main aim of this study was to develop and implement an algorithm for the rapid, accurate and automated identification of paths leading from buried protein clefts, pockets and cavities in dynamic and static protein structures to the outside solvent.

Results: The algorithm to perform a skeleton search was based on a reciprocal distance function grid that was developed and implemented for the CAVER program. The program identifies and visualizes routes from the interior of the protein to the bulk solvent. CAVER was primarily developed for proteins, but the algorithm is sufficiently robust to allow the analysis of any molecular system, including nucleic acids or inorganic material. Calculations can be performed using discrete structures from crystallographic analysis and NMR experiments as well as with trajectories from molecular dynamics simulations. The fully functional program is available as a stand-alone version and as plug-in for the molecular modeling program PyMol. Additionally, selected functions are accessible in an online version.

Conclusion: The algorithm developed automatically finds the path from a starting point located within the interior of a protein. The algorithm is sufficiently rapid and robust to enable routine analysis of molecular dynamics trajectories containing thousands of snapshots. The algorithm is based on reciprocal metrics and provides an easy method to find a centerline, i.e. the spine, of complicated objects such as a protein tunnel. It can also be applied to many other molecules. CAVER is freely available from the web site http://loschmidt.chemi.muni.cz/caver/.

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Figures

Figure 1

Figure 1

Sketch of the method implemented in CAVER. The black bold circle represents the starting point. The protein is visualized by gray circles with van der Walls atom radii mapped on a discrete grid (black dots). The solid line represents the boundary between the protein (convex hull) interior and its surroundings. Empty circles represent the maximally inscribed balls on the probable route (dashed line).

Figure 2

Figure 2

Evaluation of grid nodes by cost function. A grid point evaluation using the cost function (Eq. 3). The line represents the optimal centerline.

Figure 3

Figure 3

Access path visualized by pyMol. Visualization of the access route using the PyMol plug-in. Wires represent the protein surface, balls are nodes and the surface represents the export route.

Figure 4

Figure 4

Path profile convergence. Convergence of the path profile found on the grid with increasing precision, i.e. decreasing node distance d. Calculation of one path takes approximately 11 sec in case of d = 0.7°A (Athlon 2600+, 2GB RAM, NetBSD 1.6.1) but increases ten-fold in a substrate where d = 0.3°A.

Figure 5

Figure 5

Scheme of haloalkane dehalogenases' tunnels. Schematic representation of access paths for DhlA (A), DhaA (B) and LinB (C) identified by protein crystallography [19–31] and molecular dynamic simulations [32]. The slot in DhlA was described in this study.

Figure 6

Figure 6

Tunnels found by CAVER. Accessible paths identified by CAVER in DhlA (A), DhaA (B) and LinB (C). The most accessible tunnel in every structure (main in DhlA, upper in DhaA and lower in LinB) is colored in red. The upper tunnel of LinB is in blue. Slots are highlighted in green for each structure.

Figure 7

Figure 7

Tunnels' gorges as found by CAVER in MD trajectories. Analysis of snapshots taken from a molecular dynamics simulation of DhlA (A), DhaA (B) and LinB (C). Two clusters of tunnel gorges were identified in DhlA simulation (denoted by the numbers 1 and 2). Three clusters were identified in the DhaA simulation (denoted by the numbers 1–3) and one cluster was identified in the LinB simulation. Tunnel gorges are represented by small balls. Ball color correlates with gorge radius, balls representing narrow gorges are red and wide gorges are blue. The mesh represents the protein surface.

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