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Homology modeling and molecular dynamics based insights into Chalcone synthase and Chalcone isomerase in Phyllanthus emblica L.

ABSTRACT: Chalcone synthase (CHS) and chalcone isomerase (CHI) plays a major role in the biosynthesis of flavonoid in plants. In this study, we made extensive bioinformatics analysis to gain functional and structural insight into PeCHS and PeCHI proteins. The phylogenetic distribution of PeCHS and PeCHI genes encoding proteins demonstrated the close evolutionary relationship with different CHS and CHI proteins of other dicot plants. MicroRNA target analysis showed miR169n and 3p miR5053 targeting PeCHS gene while miR169c-3p and miR4248 are targeting PeCHI gene, respectively. Three-dimensional structural models of PeCHS and PeCHI proteins were elucidated by homology modeling with Ramachandran plots showing the excellent geometry of the proteins structure. Molecular docking revealed that cinnamoyl-coa and naringenin chalcone substrates are strongly bound to PeCHS and PeCHI proteins, respectively. Finally, molecular dynamics (MD) simulation for 30 ns, further yielded stability checks of ligands in the binding pocket and behavior of protein complexes. Thus MD simulation and interaction fraction analysis showed the stable conformation of PeCHS and PeCHI proteins with their respective substrates during theee simulation. Our study provides first-hand structural prospective of PeCHS and PeCHI proteins towards understanding the mechanism of flavonoid biosynthetic pathway in P. emblica.

SUBMITTER: Kumar A

PROVIDER: S-EPMC7403374 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:We have modeled the structure of human lymphotactin (hLpnt), by homology modeling and molecular dynamics simulations. This chemokine is unique in having a single disulfide bond and a long C-terminal tail. Because other structural classes of chemokines have two pairs of Cys residues, compared to one in Lpnt, and because it has been shown that both disulfide bonds are required for stability and function, the question arises how the Lpnt maintains its structural integrity. The initial structure of hLpnt was constructed by homology modeling. The first 63 residues in the monomer of hLpnt were modeled using the structure of the human CC chemokine, RANTES, whose sequence appeared most similar. The structure of the long C-terminal tail, missing in RANTES, was taken from the human muscle fatty-acid binding protein. In a Protein Data Bank search, this protein was found to contain a sequence that was most homologous to the long tail. Consequently, the modeled hLpnt C-terminal tail consisted of both alpha-helical and beta-motifs. The complete model of the hLpnt monomer consisted of two alpha-helices located above the five-stranded beta-sheet. Molecular dynamics simulations of the solvated initial model have indicated that the stability of the predicted fold is related to the geometry of Pro78. The five-stranded beta-sheet appeared to be preserved only when Pro78 was modeled in the cis conformation. Simulations were also performed both for the C-terminal truncated forms of the hLpnt that contained one or two (CC chemokine-like) disulfide bonds, and for the chicken Lpnt (cLpnt). Our MD simulations indicated that the turn region (T30-G34) in hLpnt is important for the interactions with the receptor, and that the long C-terminal region stabilizes both the turn (T30-G34) and the five-stranded beta-sheet. The major conclusion from our theoretical studies is that the lack of one disulfide bond and the extension of the C-terminus in hLptn are mutually complementary. It is very likely that removal of two Cys residues sufficiently destabilizes the structure of a chemokine molecule, particularly the core beta-sheet, to abolish its biological function. However, this situation is rectified by the long C-terminal segment. The role of this long region is most likely to stabilize the first beta-turn region and alpha-helix H1, explaining how this chemokine can function with a single disulfide bond.

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Homology modeling and molecular dynamics based insights into Chalcone synthase and Chalcone isomerase in Phyllanthus emblica L.

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