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

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.

Structure of the V. cholerae Na+-pumping NADH:quinone oxidoreductase

“…Most of the outliers are located in the integral membrane subunits or areas where the electron density was less well defined. Cavities and putative channels were calculated with CAVER 51 , and surface potential was calculated with APBS 52 . All figures were pre pared with PyMol 53 .…”

Structural basis of the regulatory mechanism of the plant CIPK family of protein kinases controlling ion homeostasis and abiotic stress

“…4A). Interestingly, the visual and automatic analyses of the CIPK23ΔC T190D and CIPK24/SOS2ΔC T168D molecular surfaces using CAVER (48) reveal that the ATP cavity spans linearly, wrapping the kinase domain around the hinge region between the N and C lobes (Fig. 4A).…”

A Barley Efflux Transporter Operates in a Na+-Dependent Manner, as Revealed by a Multidisciplinary Platform

“…Importantly, the disposition of pores in the Bot1 model and in the uracil/H + symporter structure, the latter used as an initial template for simulations, showed similar spatial characteristics. Evaluations of predicted pore dimensions of Bot1 (Chovancova et al, 2012) revealed that in the wild-type and mutagenized variants with preserved transport function, the pores penetrated through the a-helical bundle, while only short tunnels were formed in non-transporting variants (Supplemental Tables 2 and 3 and Supplemental Figure 8). …”

“…The dimensions of pores in wild-type and variants of Bot1 were calculated by Caver3.0 (Chovancova et al, 2012) using an ensemble of 50 snapshots deduced from each trajectory. Identified pores resulted from a series of associated spheres and sphere radii and corresponded to the closest distances to protein atoms.…”