Solvent quality and solvent polarity in polypeptides

Foumthuim, Cedrix J. Dongmo; Giacometti, Andrea

doi:10.1039/d2cp05214h

Cited by 7 publications

(3 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…An aqueous environment is essential for life as we know it, and water is a prerequisite for nearly all biochemical processes at the molecular level. Water can influence the folding of proteins, − their dynamics, and actively participate in chemical transformations . Proteins can utilize water molecules in various ways: as proton donors or receivers, molecular stabilizers, molecular lubricants enhancing protein dynamics, and as significant contributors behind the enthalpy–entropy compensation in protein–ligand binding .…”

Section: Introductionmentioning

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

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

Section: Introductionmentioning

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

“…An aqueous environment is essential for life as we know it, and water is a prerequisite for nearly all biochemical processes at a molecular level. Water can influence the folding of proteins, [1][2][3] their dynamics, 4 and actively participate in chemical transformations. 5 Proteins can utilize water molecules in various ways: as proton donors or receivers, 6 molecular stabilizers, 7 molecular lubricants enhancing protein dynamics, 8 and as significant contributors behind the enthalpyentropy compensation in protein-ligand binding.…”

Section: Introductionmentioning

confidence: 99%

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

Sequeiros-Borja

Thirunavukarasu

Foumthuim

et al. 2023

Preprint

Self Cite

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

“…Due to high computational cost, explicit models are oen limited to a solute consisting of few tens of atoms interacting with a few hundreds of small solvent molecules. 27,28 Computed free energies are shown to be force eld dependent 12,29 especially in case of urea and TMAO which are the most widely studied solvents to investigate co-solvent effects on protein stability. 30 Nevertheless, to obtain a generic model for a range of stabilizing to destabilizing solvents 31,32 consistency measures would play a factor 33 while choosing a force eld that might have been parameterized to predict a particular physical phenomenon.…”

Section: Introductionmentioning

confidence: 99%