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      CAVER 3.0: A Tool for the Analysis of Transport Pathways in Dynamic Protein Structures

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          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.

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          Most cited references 53

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          VMD: visual molecular dynamics.

          VMD is a molecular graphics program designed for the display and analysis of molecular assemblies, in particular biopolymers such as proteins and nucleic acids. VMD can simultaneously display any number of structures using a wide variety of rendering styles and coloring methods. Molecules are displayed as one or more "representations," in which each representation embodies a particular rendering method and coloring scheme for a selected subset of atoms. The atoms displayed in each representation are chosen using an extensive atom selection syntax, which includes Boolean operators and regular expressions. VMD provides a complete graphical user interface for program control, as well as a text interface using the Tcl embeddable parser to allow for complex scripts with variable substitution, control loops, and function calls. Full session logging is supported, which produces a VMD command script for later playback. High-resolution raster images of displayed molecules may be produced by generating input scripts for use by a number of photorealistic image-rendering applications. VMD has also been expressly designed with the ability to animate molecular dynamics (MD) simulation trajectories, imported either from files or from a direct connection to a running MD simulation. VMD is the visualization component of MDScope, a set of tools for interactive problem solving in structural biology, which also includes the parallel MD program NAMD, and the MDCOMM software used to connect the visualization and simulation programs. VMD is written in C++, using an object-oriented design; the program, including source code and extensive documentation, is freely available via anonymous ftp and through the World Wide Web.
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            The structure of the potassium channel: molecular basis of K+ conduction and selectivity.

            The potassium channel from Streptomyces lividans is an integral membrane protein with sequence similarity to all known K+ channels, particularly in the pore region. X-ray analysis with data to 3.2 angstroms reveals that four identical subunits create an inverted teepee, or cone, cradling the selectivity filter of the pore in its outer end. The narrow selectivity filter is only 12 angstroms long, whereas the remainder of the pore is wider and lined with hydrophobic amino acids. A large water-filled cavity and helix dipoles are positioned so as to overcome electrostatic destabilization of an ion in the pore at the center of the bilayer. Main chain carbonyl oxygen atoms from the K+ channel signature sequence line the selectivity filter, which is held open by structural constraints to coordinate K+ ions but not smaller Na+ ions. The selectivity filter contains two K+ ions about 7.5 angstroms apart. This configuration promotes ion conduction by exploiting electrostatic repulsive forces to overcome attractive forces between K+ ions and the selectivity filter. The architecture of the pore establishes the physical principles underlying selective K+ conduction.
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              Molecular dynamics simulations of biomolecules.

              Molecular dynamics simulations are important tools for understanding the physical basis of the structure and function of biological macromolecules. The early view of proteins as relatively rigid structures has been replaced by a dynamic model in which the internal motions and resulting conformational changes play an essential role in their function. This review presents a brief description of the origin and early uses of biomolecular simulations. It then outlines some recent studies that illustrate the utility of such simulations and closes with a discussion of their ever-increasing potential for contributing to biology.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Comput Biol
                PLoS Comput. Biol
                plos
                ploscomp
                PLoS Computational Biology
                Public Library of Science (San Francisco, USA )
                1553-734X
                1553-7358
                October 2012
                October 2012
                18 October 2012
                : 8
                : 10
                Affiliations
                [1 ]Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University, Brno, Czech Republic
                [2 ]Human Computer Interaction Laboratory, Faculty of Informatics, Masaryk University, Brno, Czech Republic
                [3 ]International Centre for Clinical Research, St. Anne's University Hospital Brno, Brno, Czech Republic
                UCSD, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: EC AP PB OS JB BK AG VS MK PM LB JS JD. Performed the experiments: EC AP PB JB AG MK LB. Analyzed the data: EC AP JB JD. Wrote the paper: EC AP JB LB JD. Contributed the software code: AP PB OS BK VS PM JS. Edited the manuscript: PB OS BK AG VS MK PM JS. Prepared manual and examples: EC AP JB VS.

                Article
                PCOMPBIOL-D-12-00584
                10.1371/journal.pcbi.1002708
                3475669
                23093919

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Counts
                Pages: 12
                Funding
                This work was supported by the European Regional Development Fund (CZ.1.05/2.1.00/01.0001 and CZ.1.05/1.1.00/02.0123), the Grant Agency of the Czech Republic (P202/10/1435 and P503/12/0572) and the Grant Agency of the Czech Academy of Sciences (IAA401630901). MetaCentrum provided access to computing facilities, supported by the Ministry of Education of the Czech Republic (LM2010005). The work of AG was supported by SoMoPro programme No. SIGA762 funded by the European Community within the 7th FP under grant agreement No. 229603, and cofinanced by the South Moravian Region. The work of AP was supported by Brno Ph.D. Talent Scholarship provided by Brno City Municipality. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Biochemistry
                Computational Biology
                Theoretical Biology
                Chemistry
                Theoretical Chemistry
                Physics
                Biophysics

                Quantitative & Systems biology

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