AQUA-DUCT 1.0: structural and functional analysis of macromolecules from an intramolecular voids perspective

Magdziarz, Tomasz; Mitusińska, Karolina; Bzówka, Maria; Raczyńska, Agata; Stańczak, Agnieszka; Banas, Michał; Bagrowska, Weronika; Góra, Artur

doi:10.1093/bioinformatics/btz946

Cited by 31 publications

(44 citation statements)

References 12 publications

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“…The small molecules tracking approach was used to determine the accessibility of the active site pocket in both SARS-CoV and SARS-CoV-2 Mpros, and a local distribution approach was used to provide information about an overall distribution of solvent in the proteins' interior. To properly examine the flexibility of both active site cavities, we used the time-window mode implemented in AQUA-DUCT software [30] to analyse the water molecules' flow through the cavity in a 10 ns time step and combined that with the outer pocket calculations to examine the plasticity and maximal accessible volume (MAV) of the binding cavity.…”

Section: Plasticity Of the Binding Cavitiesmentioning

confidence: 99%

“…The AQUA-DUCT 1.0 software [30] was used to track water and cosolvent molecules. Molecules of interest, which entered the so-called Object, defined as a 5 Å sphere around the centre of geometry of active site residues, namely, H41, C145, H164, and D187, were traced within the Scope region, defined as the interior of a convex hull of both COVID-19 Mpro and SARS Mpro Cα atoms.…”

Section: Water and Cosolvent Molecule Trackingmentioning

confidence: 99%

“…AQUA-DUCT was used to analyse maximal accessible volume (MAV), defined as the outer pocket [30]. Pockets were calculated by analysis of paths found during molecules tracking step in AQUA-DUCT.…”

Section: Water and Cosolvent Molecule Trackingmentioning

confidence: 99%

“…AQUA-DUCT [30] was used to detect regions occupied by molecules of interest, as well as to identify the densest sites using a local solvent distribution approach. Those so-called hot-spots could be calculated as local and/or global, on the basis of the distribution of tracked molecules that visited the Object (local) or just the Scope without visiting the Object (global); here, they were considered as potential binding sites.…”

Section: Hot-spot Identification and Selectionmentioning

confidence: 99%

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Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design

Bzówka

Mitusińska

Raczyńska

et al. 2020

IJMS

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156

194

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The novel coronavirus whose outbreak took place in December 2019 continues to spread at a rapid rate worldwide. In the absence of an effective vaccine, inhibitor repurposing or de novo drug design may offer a longer-term strategy to combat this and future infections due to similar viruses. Here, we report on detailed classical and mixed-solvent molecular dynamics simulations of the main protease (Mpro) enriched by evolutionary and stability analysis of the protein. The results were compared with those for a highly similar severe acute respiratory syndrome (SARS) Mpro protein. In spite of a high level of sequence similarity, the active sites in both proteins showed major differences in both shape and size, indicating that repurposing SARS drugs for COVID-19 may be futile. Furthermore, analysis of the binding site's conformational changes during the simulation time indicated its flexibility and plasticity, which dashes hopes for rapid and reliable drug design. Conversely, structural stability of the protein with respect to flexible loop mutations indicated that the virus' mutability will pose a further challenge to the rational design of small-molecule inhibitors. However, few residues contribute significantly to the protein stability and thus can be considered as key anchoring residues for Mpro inhibitor design.

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Section: Plasticity Of the Binding Cavitiesmentioning

confidence: 99%

Section: Water and Cosolvent Molecule Trackingmentioning

confidence: 99%

Section: Water and Cosolvent Molecule Trackingmentioning

confidence: 99%

Section: Hot-spot Identification and Selectionmentioning

confidence: 99%

See 2 more Smart Citations

Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design

Bzówka

Mitusińska

Raczyńska

et al. 2020

IJMS

Self Cite

156

194

View full text Add to dashboard Cite

show abstract

“…The paths of the solvent diffusion to and from the active site area (within a radius of 4Å from the catalytic triad) to the surface of the protein were analyzed using AQUA-DUCT software (49). Aqua-duct is a tool to perform a detailed analysis of solvent access and channels in proteins.…”

Section: Water Pathway and Analysismentioning

confidence: 99%

Activation and selectivity of OTUB-1 and OTUB-2 deubiquitinylases

Sivakumar¹,

Kumar²,

Naumann³

et al. 2020

Journal of Biological Chemistry

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The ovarian tumor domain (OTU) deubiquitinylating cysteine proteases OTUB1 and OTUB2 (OTU ubiquitin aldehyde binding 1 and 2) are representative members of the OTU subfamily of deubiquitinylases. Deubiquitinylation critically regulates a multitude of important cellular processes, such as apoptosis, cell signaling, and growth. Moreover, elevated OTUB expression has been observed in various cancers, including glioma, endometrial cancer, ovarian cancer, and breast cancer. Here, using molecular dynamics simulation approaches, we found that both OTUB1 and OTUB2 display a catalytic triad characteristic of proteases but differ in their configuration and protonation states. The OTUB1 protein had a prearranged catalytic site, with strong electrostatic interactions between the active-site residues His265 and Asp267. In OTUB2, however, the arrangement of the catalytic triad was different. In the absence of ubiquitin, the neutral states of the catalytic-site residues in OTUB2 were more stable, resulting in larger distances between these residues. Only upon ubiquitin binding did the catalytic triad in OTUB2 rearrange and bring the active site into a catalytically feasible state. An analysis of water access channels revealed only a few diffusion trajectories for the catalytically active form of OTUB1, whereas in OTUB2 the catalytic site was solvent-accessible, and a larger number of water molecules reached and left the binding pocket. Interestingly, in OTUB2, the catalytic residues His224 and Asn226 formed a stable hydrogen bond. We propose that the observed differences in activation kinetics, protonation states, water channels, and active-site accessibility between OTUB1 and OTUB2 may be relevant for the selective design of OTU inhibitors.

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Multiresolution molecular dynamics simulations reveal the interplay between conformational variability and functional interactions in membrane‐bound cytochrome P450 2B4

Han,

Teuffel,

Mukherjee

et al. 2024

Protein Science

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Cytochrome P450 2B4 (CYP 2B4) is one of the best‐characterized CYPs and serves as a key model system for understanding the mechanisms of microsomal class II CYPs, which metabolize most known drugs. The highly flexible nature of CYP 2B4 is apparent from crystal structures that show the active site with either a wide open or a closed heme binding cavity. Here, we investigated the conformational ensemble of the full‐length CYP 2B4 in a phospholipid bilayer, using multiresolution molecular dynamics (MD) simulations. Coarse‐grained MD simulations revealed two predominant orientations of CYP 2B4's globular domain with respect to the bilayer. Their refinement by atomistic resolution MD showed adaptation of the enzyme's interaction with the lipid bilayer, leading to open configurations that facilitate ligand access to the heme binding cavity. CAVER analysis of enzyme tunnels, AquaDuct analysis of water routes, and Random Acceleration Molecular Dynamics simulations of ligand dissociation support the conformation‐dependent passage of molecules between the active site and the protein surroundings. Furthermore, simulation of the re‐entry of the inhibitor bifonazole into the open conformation of CYP 2B4 resulted in binding at a transient hydrophobic pocket within the active site cavity that may play a role in substrate binding or allosteric regulation. Together, these results show how the open conformation of CYP 2B4 facilitates the binding of substrates from and release of products to the membrane, whereas the closed conformation prolongs the residence time of substrates or inhibitors and selectively allows the passage of smaller reactants via the solvent and water channels.

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AQUA-DUCT 1.0: structural and functional analysis of macromolecules from an intramolecular voids perspective

Cited by 31 publications

References 12 publications

Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design

Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design

Activation and selectivity of OTUB-1 and OTUB-2 deubiquitinylases

Multiresolution molecular dynamics simulations reveal the interplay between conformational variability and functional interactions in membrane‐bound cytochrome P450 2B4

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