Evaluation of lipase access tunnels and analysis of substance transport in comparison with experimental data

Melo, Jéssica Jéssi Carvalho de; Gonçalves, Jesica Ribeiro; Brandão, Luma Mirely de Souza; Souza, Ranyere Lucena de; Pereira, Matheus M.; Lima, Álvaro Silva; Soares, Cleide Mara Faria

doi:10.1007/s00449-022-02731-x

Cited by 6 publications

(6 citation statements)

References 55 publications

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Section: Resultssupporting

confidence: 75%

“…The results also show numerous new tunnels that transport water, albeit in smaller quantities, which may correspond to the outliers observed by Mitusińska et al ( Figures S8c,d and S9 ). Lip results showed predominant water transport in the main tunnel described in previous studies 64–67 ( Figure S10a,b and Table S1 ). Additionally, several important tunnels for water transport were identified, most in the same region of the main tunnel ( Figure S10c,d ) and fewer in different regions ( Figure S11 ).…”

Section: Resultssupporting

confidence: 74%

“…These atoms were selected for two reasons: first, their center of geometry presented one of the lowest root mean square fluctuation (RMSF), and second, this center of geometry was inside the deepest part of the cavities described in the literature for each protein. [61][62][63][64][65][66][67][68][69][70] Furthermore, to achieve consistent tunnel entrances, HDBSCAN v0.8.27 71 was employed at the tunnel endpoints for clustering with the following parameters: cluster_selectioin_epsilon of 1.5, allow_single_cluster to True, min_samples and min_cluster_size to 5. Then, the formed clusters were taken as independent tunnels, and the tunnels identified as noise were discarded.…”

Section: Tunnel Network and Water Transport Analysesmentioning

confidence: 99%

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

Sequeiros-Borja

Thirunavukarasu

Foumthuim

et al. 2023

Preprint

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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.

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Section: Resultssupporting

confidence: 75%

Section: Resultssupporting

confidence: 74%

Section: Tunnel Network and Water Transport Analysesmentioning

confidence: 99%

See 1 more Smart Citation

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

Sequeiros-Borja

Thirunavukarasu

Foumthuim

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…The results also show numerous new tunnels that transport water, albeit in smaller quantities, which may correspond to the outliers observed by Mitusińska et al (Figures S8c,d and S9). Lip results showed predominant water transport in the main tunnel described in previous studies − (Figure S10a,b and Table S1). Additionally, several important tunnels for water transport were identified, most in the same region of the main tunnel (Figure S10c,d) and fewer in different regions (Figure S11).…”

Section: Resultssupporting

confidence: 73%

“…The remaining parameters were left as default. These atoms were selected based on their center of geometry, presenting one of the lowest root-mean-square fluctuations (RMSF) and being inside the deepest part of the cavities described in the literature for each protein. − To achieve consistent tunnel entrances, HDBSCAN v0.8.27 was used at the tunnel end points for clustering, with the following parameters: cluster_selection_epsilon of 1.5, allow_single_cluster set to True, and min_samples and min_cluster_size set to 5. The formed clusters were considered independent tunnels, and the tunnels identified as noise were discarded.…”

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.

show abstract

Improving efficiency and reducing enzyme inactivation during lipase-mediated epoxidation of α-pinene in a double-phase reaction system

Yu,

Zou,

et al. 2023

Bioprocess Biosyst Eng

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Evaluation of lipase access tunnels and analysis of substance transport in comparison with experimental data

Cited by 6 publications

References 55 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

Improving efficiency and reducing enzyme inactivation during lipase-mediated epoxidation of α-pinene in a double-phase reaction system

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