Limits...
CAVER 3.0: a tool for the analysis of transport pathways in dynamic protein structures.

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 - PLoS Comput. Biol. (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University, Brno, Czech Republic.

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.

Show MeSH
Bottleneck dynamics and structural basis of gating in the p1 tunnel of DhaA.(A) The bottleneck 1 represents the most frequent bottleneck of the p1 tunnel and is mostly formed by Ala145, Phe149, Ala172 and Cys176. Comparison of snapshots with an open (red) and closed (blue) p1 tunnels suggested that the gating is mediated by: (i) movement of the N-terminal part of the cap domain carrying Ala145 and Phe149; (ii) movement of the α5-helix with Cys176 and Ala172; and (iii) conformational change of the bottleneck residues Phe149 and Cys176. The bottleneck radius in the selected snapshots with an open and closed tunnel was 2.3 Å and 0.9 Å, respectively. (B) The bottleneck 2 of the p1 tunnel is mostly formed by Thr148, Ala172 and Lys175. Comparison of snapshots with an open (red) and closed (green) p1 tunnel suggested that gating is mediated by: (i) movement of the N-terminal part of the cap domain carrying Thr148; (ii) movement of the α5-helix carrying Ala172; and (iii) the conformational change of the bottleneck residues Thr148 and Lys175. The bottleneck radius in the selected snapshot with an open and closed tunnel was 2.3 Å and 0.9 Å, respectively.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3475669&req=5

pcbi-1002708-g005: Bottleneck dynamics and structural basis of gating in the p1 tunnel of DhaA.(A) The bottleneck 1 represents the most frequent bottleneck of the p1 tunnel and is mostly formed by Ala145, Phe149, Ala172 and Cys176. Comparison of snapshots with an open (red) and closed (blue) p1 tunnels suggested that the gating is mediated by: (i) movement of the N-terminal part of the cap domain carrying Ala145 and Phe149; (ii) movement of the α5-helix with Cys176 and Ala172; and (iii) conformational change of the bottleneck residues Phe149 and Cys176. The bottleneck radius in the selected snapshots with an open and closed tunnel was 2.3 Å and 0.9 Å, respectively. (B) The bottleneck 2 of the p1 tunnel is mostly formed by Thr148, Ala172 and Lys175. Comparison of snapshots with an open (red) and closed (green) p1 tunnel suggested that gating is mediated by: (i) movement of the N-terminal part of the cap domain carrying Thr148; (ii) movement of the α5-helix carrying Ala172; and (iii) the conformational change of the bottleneck residues Thr148 and Lys175. The bottleneck radius in the selected snapshot with an open and closed tunnel was 2.3 Å and 0.9 Å, respectively.

Mentions: The most frequent bottleneck in the DhaA p1 tunnel is formed mainly by Phe149 (71% of p1 tunnels), Cys176 (59%), Ala172 (50%) and Ala145 (38%) residues, mostly in combinations Ala145-Phe149-Cys176 and Phe149-Ala172-Cys176 (26% and 24% of all p1 pathways, respectively). Comparison of structures with an open and closed p1 tunnels suggested that the gating in this bottleneck is mediated by the movement of the N-terminal part of the cap domain (Glu139-Phe149) carrying the bottleneck residues Ala145 and Phe149, movement of the C-terminal part of the α5-helix with the bottleneck residue Cys176, and by the conformational change of the bottleneck residues Phe149 and Cys176 (Figure 5A). The proposed structural basis of gating in the bottleneck is in agreement with the results from RAMD analysis [15].


CAVER 3.0: a tool for the analysis of transport pathways in dynamic protein structures.

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 - PLoS Comput. Biol. (2012)

Bottleneck dynamics and structural basis of gating in the p1 tunnel of DhaA.(A) The bottleneck 1 represents the most frequent bottleneck of the p1 tunnel and is mostly formed by Ala145, Phe149, Ala172 and Cys176. Comparison of snapshots with an open (red) and closed (blue) p1 tunnels suggested that the gating is mediated by: (i) movement of the N-terminal part of the cap domain carrying Ala145 and Phe149; (ii) movement of the α5-helix with Cys176 and Ala172; and (iii) conformational change of the bottleneck residues Phe149 and Cys176. The bottleneck radius in the selected snapshots with an open and closed tunnel was 2.3 Å and 0.9 Å, respectively. (B) The bottleneck 2 of the p1 tunnel is mostly formed by Thr148, Ala172 and Lys175. Comparison of snapshots with an open (red) and closed (green) p1 tunnel suggested that gating is mediated by: (i) movement of the N-terminal part of the cap domain carrying Thr148; (ii) movement of the α5-helix carrying Ala172; and (iii) the conformational change of the bottleneck residues Thr148 and Lys175. The bottleneck radius in the selected snapshot with an open and closed tunnel was 2.3 Å and 0.9 Å, respectively.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3475669&req=5

pcbi-1002708-g005: Bottleneck dynamics and structural basis of gating in the p1 tunnel of DhaA.(A) The bottleneck 1 represents the most frequent bottleneck of the p1 tunnel and is mostly formed by Ala145, Phe149, Ala172 and Cys176. Comparison of snapshots with an open (red) and closed (blue) p1 tunnels suggested that the gating is mediated by: (i) movement of the N-terminal part of the cap domain carrying Ala145 and Phe149; (ii) movement of the α5-helix with Cys176 and Ala172; and (iii) conformational change of the bottleneck residues Phe149 and Cys176. The bottleneck radius in the selected snapshots with an open and closed tunnel was 2.3 Å and 0.9 Å, respectively. (B) The bottleneck 2 of the p1 tunnel is mostly formed by Thr148, Ala172 and Lys175. Comparison of snapshots with an open (red) and closed (green) p1 tunnel suggested that gating is mediated by: (i) movement of the N-terminal part of the cap domain carrying Thr148; (ii) movement of the α5-helix carrying Ala172; and (iii) the conformational change of the bottleneck residues Thr148 and Lys175. The bottleneck radius in the selected snapshot with an open and closed tunnel was 2.3 Å and 0.9 Å, respectively.
Mentions: The most frequent bottleneck in the DhaA p1 tunnel is formed mainly by Phe149 (71% of p1 tunnels), Cys176 (59%), Ala172 (50%) and Ala145 (38%) residues, mostly in combinations Ala145-Phe149-Cys176 and Phe149-Ala172-Cys176 (26% and 24% of all p1 pathways, respectively). Comparison of structures with an open and closed p1 tunnels suggested that the gating in this bottleneck is mediated by the movement of the N-terminal part of the cap domain (Glu139-Phe149) carrying the bottleneck residues Ala145 and Phe149, movement of the C-terminal part of the α5-helix with the bottleneck residue Cys176, and by the conformational change of the bottleneck residues Phe149 and Cys176 (Figure 5A). The proposed structural basis of gating in the bottleneck is in agreement with the results from RAMD analysis [15].

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University, Brno, Czech Republic.

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.

Show MeSH