Molecular dynamics, residue network analysis, and cross-correlation matrix to characterize the deleterious missense mutations in GALE causing galactosemia III

Kumar, Sanjit; Sankar, Srivarshini; Kumar, Dileep; Younes, Salma; Younes, Nadin; Siva, Ramamoorthy; C, George Priya Doss; Zayed, Hatem

doi:10.1007/s12013-020-00960-z

Cited by 31 publications

(10 citation statements)

References 74 publications

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“…The remaining hit molecules showed an average (~1–3) H‐bonds (Figure 6B). As the protein functions through cumulative atomic motions, the PCA 10,49–51 study was employed to understand the movements of the Cα atoms structurally for the five complexes. Based on the cumulative motion of the complexes, the first and last principal components were employed to construct the PCA graph.…”

Section: Resultsmentioning

confidence: 99%

Identification of potential inhibitors, conformational dynamics, and mechanistic insights into mutant Kirsten rat sarcoma virus (G13D) driven cancers

Tayubi

2022

J of Cellular Biochemistry

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The mutations at the hotspot region of K‐Ras result in the progression of cancer types. Our study aimed to explore the small molecule inhibitors against the G13D mutant K‐Ras model with anti‐cancerous activity from food and drug administration (FDA)‐approved drug compounds. We implemented several computational strategies such as pharmacophore‐based virtual screening, molecular docking, absorption, distribution, metabolism and excretion features, and molecular simulation to ensure the identified hit compounds have potential efficacy against G13D K‐Ras. We found that the FDA‐approved compounds, namely, azelastine, dihydrocodeine, paroxetine, and tramadol, are potential candidates to inhibit the action of G13D mutant K‐Ras. All four compounds exhibited similar binding patterns of sotorasib, and a structural binding mechanism with significant hydrophobic contacts. The descriptor features from the QikProp of all four compounds are within allowable limits compared to sotorasib drug. Consequently, a molecular simulation result emphasized that the dihydrocodeine and tramadol exhibited less fluctuation, minimal basin, significant h‐bonds, and potent inhibition against G13D K‐Ras. As a result, the current research identifies prospective K‐Ras inhibitors that could be further improved with biochemical analysis for precision medicine against K‐Ras‐driven cancers.

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Section: Resultsmentioning

confidence: 99%

Identification of potential inhibitors, conformational dynamics, and mechanistic insights into mutant Kirsten rat sarcoma virus (G13D) driven cancers

Tayubi

2022

J of Cellular Biochemistry

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“…We found that Rg was greater in the R248 mutant-p53–DNA complexes than in the wt-p53–DNA complex, signifying a decline in the compactness of the mutant- p53–DNA complexes ( Figure 4 ). The above analyses show that the protein’s structural compactness reduces with a decrease in H-bonds [ 68 ].…”

Section: Discussionmentioning

confidence: 99%

Unraveling the Structural Changes in the DNA-Binding Region of Tumor Protein p53 (TP53) upon Hotspot Mutation p53 Arg248 by Comparative Computational Approach

Balasundaram

2022

IJMS

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The vital tissue homeostasis regulator p53 forms a tetramer when it binds to DNA and regulates the genes that mediate essential biological processes such as cell-cycle arrest, senescence, DNA repair, and apoptosis. Missense mutations in the core DNA-binding domain (109–292) simultaneously cause the loss of p53 tumor suppressor function and accumulation of the mutant p53 proteins that are carcinogenic. The most common p53 hotspot mutation at codon 248 in the DNA-binding region, where arginine (R) is substituted by tryptophan (W), glycine (G), leucine (L), proline (P), and glutamine (Q), is reported in various cancers. However, it is unclear how the p53 Arg248 mutation with distinct amino acid substitution affects the structure, function, and DNA binding affinity. Here, we characterized the pathogenicity and protein stability of p53 hotspot mutations at codon 248 using computational tools PredictSNP, Align GVGD, HOPE, ConSurf, and iStable. We found R248W, R248G, and R248P mutations highly deleterious and destabilizing. Further, we subjected all five R248 mutant-p53–DNA and wt-p53–DNA complexes to molecular dynamics simulation to investigate the structural stability and DNA binding affinity. From the MD simulation analysis, we observed increased RMSD, RMSF, and Rg values and decreased protein–DNA intermolecular hydrogen bonds in the R248-p53–DNA than the wt-p53–DNA complexes. Likewise, due to high SASA values, we observed the shrinkage of proteins in R248W, R248G, and R248P mutant-p53–DNA complexes. Compared to other mutant p53–DNA complexes, the R248W, R248G, and R248P mutant-p53–DNA complexes showed more structural alteration. MM-PBSA analysis showed decreased binding energies with DNA in all five R248-p53–DNA mutants than the wt-p53–DNA complexes. Henceforth, we conclude that the amino acid substitution of Arginine with the other five amino acids at codon 248 reduces the p53 protein’s affinity for DNA and may disrupt cell division, resulting in a gain of p53 function. The proposed study influences the development of rationally designed molecular-targeted treatments that improve p53-based therapeutic outcomes in cancer.

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“…Dynamic cross-correlation matrix (DCCM) was employed to determine the pairwise correlations of residue displacement during MD simulation, thus accessing the dynamic complicacies of the M4/5 complexes. 41 The values of C ij represent cross-correlation among residual motions i and j , as calculated by the following equation. C ij = Δ R i ·Δ R j …”

Section: Methodsmentioning

confidence: 99%

Selectivity mechanism of muscarinic acetylcholine receptor antagonism through in silico investigation

Chen

Wang

et al. 2022

Phys. Chem. Chem. Phys.

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Molecular dynamics, residue network analysis, and cross-correlation matrix to characterize the deleterious missense mutations in GALE causing galactosemia III

Cited by 31 publications

References 74 publications

Identification of potential inhibitors, conformational dynamics, and mechanistic insights into mutant Kirsten rat sarcoma virus (G13D) driven cancers

Identification of potential inhibitors, conformational dynamics, and mechanistic insights into mutant Kirsten rat sarcoma virus (G13D) driven cancers

Unraveling the Structural Changes in the DNA-Binding Region of Tumor Protein p53 (TP53) upon Hotspot Mutation p53 Arg248 by Comparative Computational Approach

Selectivity mechanism of muscarinic acetylcholine receptor antagonism through in silico investigation

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