Divide-and-conquer approach to study protein tunnels in long molecular dynamics simulations

Sequeiros-Borja, Carlos; Surpeta, Bartłomiej; Marchlewski, Igor; Brezovský, Jan

doi:10.1016/j.mex.2022.101968

Cited by 2 publications

(2 citation statements)

References 10 publications

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“…The trajectories underwent analysis using the cpptraj module of Amber18, CAVER v3.02, AQUA-DUCT v1.0.11, TransportTools v0.9.0, and Python3 in-house scripts. For the tunnel network calculations with CAVER, the divide-and-conquer approach was applied, setting the probe radius to 0.7 Å and the shell radius to 3.0 Å for Hal, Epx, hEpx, and E470G and 5.0 Å for Lip. CAVER starting atoms for the tunnel search were chosen as follows: D106-CG, W107-CD2, F168–N, and L246-N for Hal; W106-CD2, L181-N, Y235-CB, and D265-CA for Epx; G123-O, E126-CG, G342-CA, and T416-HA for Lip; and Y466-CD1 and H524-CA for hEpx and E470G.…”

Section: Methodsmentioning

confidence: 99%

Water will Find Its Way: Transport through Narrow Tunnels in Hydrolases

Sequeiros-Borja,

Surpeta,

Thirunavukarasu

et al. 2024

J. Chem. Inf. Model.

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An aqueous environment is vital for life as we know it, and water is essential for nearly all biochemical processes at the molecular level. Proteins utilize water molecules in various ways. Consequently, proteins must transport water molecules across their internal network of tunnels to reach the desired action sites, either within them or by functioning as molecular pipes to control cellular osmotic pressure. Despite water playing a crucial role in enzymatic activity and stability, its transport has been largely overlooked, with studies primarily focusing on water transport across membrane proteins. The transport of molecules through a protein's tunnel network is challenging to study experimentally, making molecular dynamics simulations the most popular approach for investigating such events. In this study, we focused on the transport of water molecules across three different α/β-hydrolases: haloalkane dehalogenase, epoxide hydrolase, and lipase. Using a 5 μs adaptive simulation per system, we observed that only a few tunnels were responsible for the majority of water transport in dehalogenase, in contrast to a higher diversity of tunnels in other enzymes. Interestingly, water molecules could traverse narrow tunnels with subangstrom bottlenecks, which is surprising given the commonly accepted water molecule radius of 1.4 Å. Our analysis of the transport events in such narrow tunnels revealed 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 the total water transport observed, emphasizing the need to surpass the standard geometrical limits on the functional tunnels to properly account for the relevant transport processes. Finally, we demonstrated 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.

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Section: Methodsmentioning

confidence: 99%

Water will Find Its Way: Transport through Narrow Tunnels in Hydrolases

Sequeiros-Borja,

Surpeta,

Thirunavukarasu

et al. 2024

J. Chem. Inf. Model.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The trajectories underwent analysis using the cpptraj 56 module of Amber18, CAVER 57 v3.02, AQUA-DUCT 58 v1.0.11, TransportTools 59 v0.9.0, and Python3 in-house scripts. For the tunnel network calculations with CAVER, the divide-and-conquer approach 60 was applied, setting the probe radius to 0.7 Å and the shell radius to 3.0 Å for Hal, Epx, hEpx, and E470G, and 5.0 Å for Lip. CAVER starting atoms for tunnel search were chosen as follows: D106-CG, W107-CD2, F168-N, and L246-N for Hal; W106-CD2, L181-N, Y235-CB, and D265-CA for Epx; G123-O, E126-CG, G342-CA, and T416-HA for Lip; Y466-CD1 and H524-CA for hEpx and E470G.…”

Section: Methodsmentioning

confidence: 99%

Water will find its way: transport through narrow tunnels in hydrolases

Sequeiros-Borja

Thirunavukarasu

Foumthuim

et al. 2023

Preprint

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View full text Add to dashboard Cite

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.

show abstract

Divide-and-conquer approach to study protein tunnels in long molecular dynamics simulations

Cited by 2 publications

References 10 publications

Water will Find Its Way: Transport through Narrow Tunnels in Hydrolases

Water will Find Its Way: Transport through Narrow Tunnels in Hydrolases

Water will find its way: transport through narrow tunnels in hydrolases

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