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Structure prediction of transferrin receptor protein 1 (TfR1) by homology modelling, docking, and molecular dynamics simulation studies.

ABSTRACT: Transferrin receptor protein 1 (TfR1) is an important molecule in anti-cancer therapy. Targeted delivery of such therapeutic compounds improves their cellular uptake and circulation time, thereby enhancing therapeutic efficacy. Drug designing is therefore used to engineer molecules with structures that facilitate specific interactions. However, this process requires a thorough knowledge of all the interactions, including the three-dimensional (3D) and quaternary structures (QS) of the interacting molecules. Since structural information is available for only a part of the full TfR1 sequence, in the present study, we predicted the whole structure of TfR1 using homology modelling, docking, and molecular dynamics simulations. Homology modelling is used to generate 3D structures of TfR1 using MODELLER, I-TASSER, and RaptorX programs. Verify3D and Rampage server evaluated the quality of the resultant models. According to this evaluation, the model built by the RaptorX server and validated by Verify3D (compatibility: 83.82%) had the highest number of residues (95.5%) within the favoured regions of the Ramachandran plot, making it the most reliable 3D protein structure for TfR1 compared with others. The QS of TfR1 was built using HADDOCK and SymmDock docking software, and the results were evaluated by the ligand root mean square deviation (l-RMSD) value computed using the ProFit software. This showed that both HADDOCK and SymmDock gave acceptable results. However, the HADDOCK result was more stable and closest to the native complex structure with disulfide bonds. Therefore, the HADDOCK complex was further refined using both SymmRef and GalaxyRefineComplex until the medium l-RMSD rank was reached. This QS was successfully verified using nanoscale molecular dynamics (NAMD) energy minimization. This model could pave the way for further functional, structural, and therapeutic studies on TfR1.

SUBMITTER: Al-Refaei MA

PROVIDER: S-EPMC6994855 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Calcium homeostasis modulator 1 (CALHM1) is a protein responsible for causing Alzheimer's disease. In the absence of an experimentally designed protein molecule, homology modelling was performed. Through homology modelling, different CALHM1 models were generated and validated through Rampage. To carry out further in silico studies, through molecular docking and molecular dynamics simulation experiments, various flavonoids and alkaloids from Bauhinia variegata were utilised as inhibitors to target the protein (CALHM1). The sequence of CALHM1 was retrieved from UniProt and the secondary structure prediction of CALHM1 was done through CFSSP, GOR4, and SOPMA methods. The structure was identified through LOMETS, MUSTER, and MODELLER and finally, the structures were validated through Rampage. Bauhinia variegata plant was used to check the interaction of alkaloids and flavonoids against CALHM1. The protein and protein-ligand complex were also validated through molecular dynamics simulations studies. The model generated through MODELLER software with 6VAM A was used because this model predicted the best results in the Ramachandran plot. Further molecular docking was performed, quercetin was found to be the most appropriate candidate for the protein molecule with the minimum binding energy of -12.45 kcal/mol and their ADME properties were analysed through Molsoft and Molinspiration. Molecular dynamics simulations showed that CALHM1 and CALHM1-quercetin complex became stable at 2500 ps. It may be seen through the study that quercetin may act as a good inhibitor for treatment. With the help of an in silico study, it was easier to analyse the 3D structure of the protein, which may be scrutinized for the best-predicted model. Quercetin may work as a good inhibitor for treating Alzheimer's disease, according to in silico research using molecular docking and molecular dynamics simulations, and future in vitro and in vivo analysis may confirm its effectiveness.

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Structure prediction of transferrin receptor protein 1 (TfR1) by homology modelling, docking, and molecular dynamics simulation studies.

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