Modeling the role of charged residues in thermophilic proteins by rotamer and dynamic cross correlation analysis

Sucharski, Fernanda; Gallo, Gloria; Coelho, Camila; Hardy, Leon; Würtele, Martin

doi:10.1007/s00894-023-05490-y

Cited by 2 publications

(2 citation statements)

References 47 publications

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“…Therefore, the direction of site selection was shifted to residues that can produce synergistic effects with the above key sites. Dynamic residue cross-correlation is often used to analyze synergistic effects between residues . It has also recently been shown that residue networks can act over long distances at enzyme active sites and are therefore useful targets for mutagenesis, so this strategy is also used here to find key target sites.…”

Section: Resultsmentioning

confidence: 99%

“…Dynamic residue cross-correlation is often used to analyze synergistic effects between residues. 32 It has also recently been shown that residue networks can act over long distances at enzyme active sites 33 and are therefore useful targets for mutagenesis, 28 so this strategy is also used here to find key target sites. Taking the 12 key residues as the analysis objective, the residue horizontal dynamic cross-correlation mapping was used to determine other dynamically coupled residues in the SS-BGL-Rd composite structure.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Residue Effect-Guided Design: Engineering of S. Solfataricus β-Glycosidase to Enhance Its Thermostability and Bioproduction of Ginsenoside Compound K

Shen,

Dalby,

Guo

et al. 2023

J. Agric. Food Chem.

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β-Glycosidase from Sulfolobus solfataricus (SS-BGL) is a highly effective biocatalyst for the synthesis of compound K (CK) from glycosylated protopanaxadiol ginsenosides. In order to improve the thermal stability of SS-BGL, molecular dynamics simulations were used to determine the residue-level binding energetics of ginsenoside Rd in the SS-BGL-Rd docked complex and to identify the top ten critical contributors. Target sites for mutations were determined using dynamic cross-correlation mapping of residues via the Ohm server to identify networks of distal residues that interact with the key binding residues. Target mutations were determined rationally based on site characteristics. Single mutants and then recombination of top hits led to the two most promising variants SS-BGL-Q96E/N97D/N302D and SS-BGL-Q96E/N97D/N128D/N302D with 2.5-fold and 3.3-fold increased half-lives at 95 °C, respectively. The enzyme activities relative to those of wild-type for ginsenoside conversion were 161 and 116%, respectively..

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Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Residue Effect-Guided Design: Engineering of S. Solfataricus β-Glycosidase to Enhance Its Thermostability and Bioproduction of Ginsenoside Compound K

Shen,

Dalby,

Guo

et al. 2023

J. Agric. Food Chem.

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Isoniazid Derivatives as Potential Lipoxygenase‐15 Inhibitors: In‐vitro and In‐silico Studies

Alghamdi,

Azam,

Jamir Anwar

et al. 2024

ChemistrySelect

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The enzymatic oxidation of polyunsaturated fatty acids, particularly arachidonic acid, produces important lipid mediators such as leukotrienes and prostaglandins, which are critical for triggering inflammatory cascades in the body. The enzyme lipoxygenase‐15 (LOX‐15) plays a crucial role in the oxygenation of unsaturated fatty acids. Targeting this enzyme for inhibition is essential for diminishing inflammation and averting numerous potentially fatal diseases. Therefore, the inhibitory activity of a series of isoniazid derivatives, selected from our in‐house library, was assessed against LOX‐15 by employing both in vitro and in silico methods. Among the 23 compounds evaluated, 15 showed activity in vitro. Notably, compound 7 was the most effective, demonstrating an IC50 value of 1.4±0.1 μM while the standard inhibitor, NDGA, showed an inhibition at 9.4±0.6 μM. These compounds were found to competitively inhibit LOX‐15, with Ki values ranging from 1.2–7.1 μM. Molecular docking was utilized to investigate the intermolecular interactions among the active compounds. The thermodynamic stability of the compound 7 and NDGA in complex with LOX‐15 was verified through 100 ns of molecular dynamics simulations. Post‐simulation analyses involved RMSD, RMSF, RoG, free energy landscape, principal component analysis, and dynamic cross‐correlation matrix. Compound 7 and NDGA had MM/GBSA binding energies of −54.14±2.55 kcal/mol and −35.24±3.23 kcal/mol, respectively. The study underscores the significant potential of isoniazid derivatives in LOX‐15 inhibition and their role in managing inflammatory diseases.

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Modeling the role of charged residues in thermophilic proteins by rotamer and dynamic cross correlation analysis

Cited by 2 publications

References 47 publications

Residue Effect-Guided Design: Engineering of S. Solfataricus β-Glycosidase to Enhance Its Thermostability and Bioproduction of Ginsenoside Compound K

Residue Effect-Guided Design: Engineering of S. Solfataricus β-Glycosidase to Enhance Its Thermostability and Bioproduction of Ginsenoside Compound K

Isoniazid Derivatives as Potential Lipoxygenase‐15 Inhibitors: In‐vitro and In‐silico Studies

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