Summary Information regarding pathways through voids in biomolecules and their roles in ligand transport is critical to our understanding of the function of many biomolecules. Recently, the advent of high-throughput molecular dynamics simulations has enabled the study of these pathways, and of rare transport events. However, the scale and intricacy of the data produced requires dedicated tools in order to conduct analyses efficiently and without excessive demand on users. To fill this gap, we developed the TransportTools, which allows the investigation of pathways and their utilization across large, simulated datasets. TransportTools also facilitates the development of custom-made analyses. Availability and Implementation TransportTools is implemented in Python3 and distributed as pip and conda packages. The source code is available at https://github.com/labbit-eu/transport_tools. Supplementary information Supplementary data are available at Bioinformatics online.
An aqueous environment is necessary for life as we know it, and water is required for almost all biochemical processes at a molecular level. Proteins employ water molecules in many ways. Hence, proteins need to transport water molecules across their internal network of tunnels to reach the desired action sites, either inside them or acting as molecular pipes to control cellular osmotic pressure. Even though water is an essential player in enzymatic activity and stability, its transport has been mostly neglected, with water transport studies mainly focused on the transport across membrane proteins. The transport of molecules through a protein's tunnel network is hard to study experimentally, rendering molecular dynamics simulations the most popular approach to study such events. In this study, we focused on the transport of water molecules across three different alpha/beta-hydrolases: haloalkane dehalogenase, epoxide hydrolase, and lipase. Employing 5 micro s adaptive simulation per system, we observed that only a few tunnels were responsible for the majority of water transport in dehalogenase, contrasting with a higher diversity of tunnels in other enzymes. Interestingly, water molecules could traverse narrow tunnels with even sub-angstrom bottlenecks, which is surprising given the commonly accepted water molecule radii of 1.4 Angstroms. Our analysis of the transport events in such narrow tunnels showed a markedly increased number of hydrogen bonds formed between the water molecules and protein, likely compensating for the steric penalty of the process. Overall, these commonly disregarded narrow tunnels accounted for ~20% of total water transport observed, highlighting the need to move past the standard geometrical limits on the functional tunnels to account for relevant transport processes properly. Finally, we showed how the obtained insights could be applied to explain the differences in a mutant of the human soluble epoxide hydrolase associated with a higher incidence of ischemic stroke.
Information regarding pathways through voids in biomolecules and their roles in ligand transport is critical to our understanding of the function of many biomolecules. Recently, the advent of high-throughput molecular dynamics simulations has enabled the study of these pathways, and of rare transport events. However, the scale and intricacy of the data produced requires dedicated tools in order to conduct analyses efficiently and without excessive demand on users. To fill this gap, we developed the TransportTools, which allows the investigation of pathways and their utilization across large, simulated datasets. TransportTools also facilitates the development of custom-made analyses. TransportTools is implemented in Python3 and distributed as pip and conda packages. The source code is available at https://github.com/labbit-eu/transport_tools.
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