Biology subjects

Thirunavukarasu, A. S.

Publications and source records attributed to Thirunavukarasu, A. S..

3 recordsLinked to original sources

bioRxiv2023

Water migration through enzyme tunnels is sensitive to choice of explicit water model

Understanding the utilization of tunnels and water transport within enzymes is crucial for the catalytic function of enzymes, as water molecules can stabilize bound substrates and help with unbinding processes of products and inhibitors. Since the choice of water models for molecular dynamics simulations was shown to determine the accuracy of various calculated properties of the bulk solvent and solvated proteins, we have investigated if and to what extent the water transport through the enzyme tunnels depends on the selection of the water model. Here, we have focused on simulating enzymes with various well-defined tunnel geometries. In a systematic investigation using haloalkane dehalogenase as a model system, we focused on the well-established TIP3P, OPC, and TIP4P-Ew water models to explore their impact on using tunnels for water molecules transport. The TIP3P water model showed significantly faster migration, resulting in the transport of approximately 2.5 times more water molecules in comparison to OPC and 2.0 times greater than the TIP4P-Ew. The increase in migration of TIP3P water molecules was mainly due to faster transit times, and in the case of narrower tunnels, greater concurrent transport was evident as well. We have observed similar behavior in two different enzymes with buried active sites and different tunnel network topologies, indicating that our findings are likely not restricted to a particular enzyme family. Our study emphasizes the critical importance of water models in comprehending the use of enzyme tunnels for small molecule transport. Given the significant role of water availability in various stages of the catalytic cycle and solvation of substrates, products, and drugs, choosing an appropriate water model might be crucial for accurate simulations of complex enzymatic reactions, rational enzyme design, and predicting drug residence times.

bioinformatics↗

bioRxiv2023

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

An aqueous environment is vital for life as we know it, and water is essential for nearly all biochemical processes at a 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 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 proteins 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 /{beta}-hydrolases: haloalkane dehalogenase, epoxide hydrolase, and lipase. Using a 5 s 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 sub-angstrom bottlenecks, which is surprising given the commonly accepted water molecule radius of 1.4 [A]. Our analysis of the transport events in such narrow tunnels revealed a markedly increased number of hydrogen bonds formed between the water molecules and the 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 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.

bioinformatics↗

bioRxiv2021

TransportTools: a library for high-throughput analyses of internal voids in biomolecules and ligand transport through them

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.

bioinformatics↗