Visibility-based approach to surface detection of tunnels in proteins

Jurčík, Adam; Sochor, Jiří­; Kozlíková, Barbora

doi:10.1145/2788539.2788548

Cited by 9 publications

(4 citation statements)

References 34 publications

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“…Finally, to provide the users with additional context, we enable to visualize the tunnel that was used by the ligand during the transportation ( R5 ). Our solution supports both the spherical representation used by CaverDock, as well as the more realistic surface representation [JBSK15] that can capture the asymmetric shape of the tunnel (see Figure 8). In both cases, the users can decide whether the tunnel should or should not be affected by the clip plane.…”

Section: Proposed Solutionsupporting

confidence: 66%

DockVis: Visual Analysis of Molecular Docking Trajectories

Furmanová

Vávra

Kozlíková

et al. 2020

Computer Graphics Forum

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Computation of trajectories for ligand binding and unbinding via protein tunnels and channels is important for predicting possible protein–ligand interactions. These highly complex processes can be simulated by several software tools, which provide biochemists with valuable information for drug design or protein engineering applications. This paper focuses on aiding this exploration process by introducing the DockVis visual analysis tool. DockVis operates with the multivariate output data from one of the latest available tools for the prediction of ligand transport, CaverDock. DockVis provides the users with several linked views, combining the 2D abstracted depictions of ligands and their surroundings and properties with the 3D view. In this way, we enable the users to perceive the spatial configurations of ligand passing through the protein tunnel. The users are initially visually directed to the most relevant parts of ligand trajectories, which can be then explored in higher detail by the follow‐up analyses. DockVis was designed in tight collaboration with protein engineers developing the CaverDock tool. However, the concept of DockVis can be extended to any other tool predicting ligand pathways by the molecular docking. DockVis will be made available to the wide user community as part of the Caver Analyst 3.0 software package (http://www.caver.cz).

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Section: Proposed Solutionsupporting

confidence: 66%

DockVis: Visual Analysis of Molecular Docking Trajectories

Furmanová

Vávra

Kozlíková

et al. 2020

Computer Graphics Forum

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“…In contrast to that study, the present findings demonstrated interactions between two major residues (Leu211 and Arg372) and the native ligand. Forming perfect residue interactions as reported in the previous study was impossible because each docking program used different algorithms to define the active sites in protein preparation and to perform molecular docking simulations [21][22]. Upon visual inspection, various Figure 2 shows the superimposition of ketoconazole on the CYP3A4 crystallographic structure and the best docking conformation.…”

Section: Validation Of the Modified Cyp3a4 Protein Structure Model Th...mentioning

confidence: 95%

Site of Metabolism (SOM) Predictions for Centella asiatica and Orthosiphon stamineus Marker Compounds with CYP3A4 Using a Molecular Docking Approach

Ridhwan

2021

MJCHEM

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The human liver enzyme CYP3A4 plays an important role in the biotransformation of xenobiotics from herbs to harmless and excretable metabolites. However, CYP3A4 catalytic activity may also produce more toxic metabolites. Predicting sites of metabolism (SOMs) in the xenobiotics may prevent unwanted CYP3A4 products. The evidence to explain the comprehensive biotransformation of major compounds from Centella asiatica and Orthosiphon stamineus is inadequate. The aim of the present study was to determine the specific interaction between CYP3A4 ferric-oxidative active sites and potential SOMs for the major chemical compounds of C. asiatica and O. stamineus. Molecular docking on CYP3A4 ferric-oxo (bound to the protoporphirin group, HEME-Fe 3+ -O -) was carried out using the CDOCKER simulation program to predict the SOMs for compounds from C. asiatica (asiaticoside, madecassoside, asiatic acid and madecassic acid) and O. stamineus (sinensetin, eupatorin and 5-hydroxy-6,7,3',4'-tetramethoxyflavone (5TMF)). Binding energies, residue-ligand interactions, and SOMs were obtained from the analysis. The molecular docking results also revealed that sinensetin, eupatorin, and 5TMF bound strongly to the CYP3A4 active site with binding energies of -22.44, -34.29, and -25.84 kcal/mol, respectively. Generally, the residues Arg106, Ile301, Ther309, Glu374 and Ala307 were identified to have the highest number of interactions with eupatorine, 5TMF and sinensetin. The SOM prediction for eupatorine showed interactions between the oxygen of the HEME iron (ferric-oxo) and the C-11 and O-4 atoms. The possible metabolism reactions were C-11-hydroxylation and O-4-demethylation. For 5TMF, the SOM prediction for interactions were at the C-13 and O-7 positions, which could undergo hydroxylation and O-demethylation reactions, respectively. The SOM of sinensetin was predicted at C-3' and the possible metabolic reaction taking place would be hydroxylation. The present study concluded that the major compounds of O. stamineus have the potential to be metabolized by CYP3A4 through hydroxylation and O-demethylation reactions. These data may be useful for phytomedicine product development related to CYP3A4 biotransformation mechanisms.

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“…Using this geometrical structure as a base, we computed a cavity surface in each frame using the algorithm described in [65]. We do not use the extension of the algorithm proposed by Jurcik et al [88] as it was developed for the detection of deeply buried voids inside proteins. While in our case the cavities in NATs are not fully surrounded by amino acids and are closer to the protein surface.…”

Section: Methodsmentioning

confidence: 99%

Dynamics-function relationship of N-terminal acetyltransferases: the β6β7 loop modulates substrate accessibility to the catalytic site

Abboud

Bedoucha

Arnesen

et al. 2018

Preprint

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23 N-terminal acetyltransferases (NATs) are enzymes catalysing the transfer of the acetyl from Ac-CoA to the 24 N-terminus of proteins, one of the most common protein modifications. Unlike NATs, lysine 25 acetyltransferases (KATs) transfer an acetyl onto the amine group of internal lysines. To date, not much is 26 known on the exclusive substrate specificity of NATs towards protein N-termini. All the NATs and some 27 KATs share a common fold called GNAT. The main difference between NATs and KATs is an extra 28 hairpin loop found only in NATs called β6β7 loop. It covers the active site as a lid. The hypothesized role of 29 the loop is that of a barrier restricting the access to the catalytic site and preventing acetylation of internal 30 lysines. We investigated the dynamics-function relationships of all available structures of NATs covering 31 the three domains of life. Using elastic network models and normal mode analysis, we found a common 32 dynamics pattern conserved through the GNAT fold; a rigid V-shaped groove, formed by the β4 and β5 33 strands and three relatively more dynamic loops α1α2, β3β4 and β6β7. We identified two independent 34 dynamical domains in the GNAT fold, which is split at the β5 strand. We characterized the β6β7 hairpin 35 loop slow dynamics and show that its movements are able to significantly widen the mouth of the ligand 36 binding site thereby influencing its size and shape. Taken together our results show that NATs may have 37 access to a broader ligand specificity range than anticipated. 38Author summary 39 N-terminal acetylation concerns 80% of eukaryotic proteins and is achieved by enzymes called the 40 N-terminal acetyltransferases (NATs). They belong to the large family of acetyltransferases and 41 adopt the GNAT fold. Interestingly most lysine acetyltransferases (KATs), which acetylate 42 specifically internal lysines, share the same fold. Rationale for the ligand recognition by the GNAT 43 enzymes remains unclear. Proteins are dynamic entities that utilize their structural flexibility to 44 carry out functions in living cells. By studying the dynamics throughout the entire NATs family, 45 we found that the slow dynamics of the fold is strongly conserved. We also revealed the mobility of 46 the active site lid, namely the -hairpin loop 67, which is one of the main structural differences between 47 the NATs and the KATs. The size and shape of the ligand binding site depend on movements of that -Dynamics-function relationship of NATs 3 48 hairpin loop. We suggest that in attempts of mapping NATs specificity or ligand design the fold flexibility 49 should be taken into consideration. 50 51 Acetyltransferases are enzymes catalysing the transfer of an acetyl group from the co-factor acetyl-52 coenzyme A (Ac-CoA) to a substrate. Among them, lysine acetyltransferases (KATs) and Nα-terminal 53 acetyltransferases (NATs) perform protein acetylation to either lysine side chains or N-termini of 54 polypeptide chains, respectively. NATs acetylate 80 to 90% of the proteins of the human ...

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Visibility-based approach to surface detection of tunnels in proteins

Cited by 9 publications

References 34 publications

DockVis: Visual Analysis of Molecular Docking Trajectories

DockVis: Visual Analysis of Molecular Docking Trajectories

Site of Metabolism (SOM) Predictions for Centella asiatica and Orthosiphon stamineus Marker Compounds with CYP3A4 Using a Molecular Docking Approach

Dynamics-function relationship of N-terminal acetyltransferases: the β6β7 loop modulates substrate accessibility to the catalytic site

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