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Water will Find Its Way: Transport through Narrow Tunnels in Hydrolases
Carlos Sequeiros-Borja1,2, Bartlomiej Surpeta1,2, Aravind Selvaram Thirunavukarasu1,2
1International Institute of Molecular and Cell Biology, Warsaw 02-109, Poland.
Journal of Chemical Information and Modeling
|April 26, 2024
Summary
Proteins transport water through narrow tunnels, challenging previous assumptions. This study reveals these overlooked pathways are crucial for biochemical processes and enzyme function.
Area of Science:
- Biochemistry
- Structural Biology
- Computational Biology
Background:
- Water is essential for life and protein function, playing key roles in enzymatic activity and stability.
- Protein-mediated water transport is crucial for cellular processes but remains understudied, especially within internal protein networks.
- Investigating molecular transport through protein tunnels is experimentally difficult, making computational simulations essential.
Purpose of the Study:
- To investigate water molecule transport through internal tunnels of three α/β-hydrolases: haloalkane dehalogenase, epoxide hydrolase, and lipase.
- To analyze the role of narrow tunnels and sub-angstrom bottlenecks in protein-mediated water transport.
- To understand the molecular mechanisms, including hydrogen bonding, that facilitate water transport through constricted protein pathways.
Main Methods:
- Utilized adaptive molecular dynamics simulations with a 5 μs duration for each enzyme system.
- Analyzed water molecule trajectories and tunnel usage across different α/β-hydrolases.
- Quantified hydrogen bond formation between water molecules and protein residues within narrow tunnels.
Main Results:
- Observed that a few tunnels dominate water transport in dehalogenase, while other enzymes show a wider distribution of active tunnels.
- Demonstrated that water molecules can successfully traverse extremely narrow tunnels with sub-angstrom bottlenecks, contrary to expectations based on water molecule size.
- Found a significant increase in hydrogen bonds within narrow tunnels, compensating for steric constraints during water transport.
- Identified that these narrow, overlooked tunnels contribute approximately 20% to the total water transport.
Conclusions:
- The study highlights the significant, often disregarded, role of narrow protein tunnels in facilitating water transport.
- Findings necessitate a re-evaluation of geometrical constraints when defining functional protein tunnels for water transport.
- The insights gained can explain functional differences in enzyme mutants, such as a human soluble epoxide hydrolase mutant linked to ischemic stroke.
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