Abstract
Tunnels and channels facilitate the transport of small molecules, ions and water solvent in a large variety of proteins. Characteristics of individual transport pathways, including their geometry, physico-chemical properties and dynamics are instrumental for understanding of structure-function relationships of these proteins, for the design of new inhibitors and construction of improved biocatalysts. CAVER is a software tool widely used for the identification and characterization of transport pathways in static macromolecular structures. Herein we present a new version of CAVER enabling automatic analysis of tunnels and channels in large ensembles of protein conformations. CAVER 3.0 implements new algorithms for the calculation and clustering of pathways. A trajectory from a molecular dynamics simulation serves as the typical input, while detailed characteristics and summary statistics of the time evolution of individual pathways are provided in the outputs. To illustrate the capabilities of CAVER 3.0, the tool was applied for the analysis of molecular dynamics simulation of the microbial enzyme haloalkane dehalogenase DhaA. CAVER 3.0 safely identified and reliably estimated the importance of all previously published DhaA tunnels, including the tunnels closed in DhaA crystal structures. Obtained results clearly demonstrate that analysis of molecular dynamics simulation is essential for the estimation of pathway characteristics and elucidation of the structural basis of the tunnel gating. CAVER 3.0 paves the way for the study of important biochemical phenomena in the area of molecular transport, molecular recognition and enzymatic catalysis. The software is freely available as a multiplatform command-line application at http://www.caver.cz.
Highlights
Proteins are highly complex systems containing a variety of clefts, grooves, protrusions and empty space in the proteins interior
Description of the software tool CAVER 3.0 was primarily developed for the analysis of protein structures, but it can be used for analysis of any molecular structure containing tunnel-like features
The individual pathways making up the collective pathways can either be visualized in a single frame, which is useful for the evaluation of the clustering results and for a general overview of the collective pathway variability, or as a molecular dynamics (MD) trajectory tracking the changes of the collective pathways over time
Summary
Proteins are highly complex systems containing a variety of clefts, grooves, protrusions and empty space in the proteins interior. This empty internal spa‘ce may form cavities of specific functions, as well as tunnels and channels (or pores), representing potential transport pathways for small molecules, ions and water molecules [1]. By channel we mean a pathway leading throughout the protein structure, without any interruption by an internal cavity, with both sides open to the surrounding solvent. Due to the internal protein dynamics, individual transport pathways and their characteristics may change significantly over time [14,17,31,32]. An ensemble of protein conformations, rather than a single static structure, have to be analyzed to get relevant information about the characteristics of individual transport pathways in a given protein [14,15,17,32,33,34]
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