Protein-Protein Interaction of Mutated Agouti Signaling Protein (ASIP) to Melanocortin Receptor 1 (MC1R) in Melanoma Skin Cancer: An Insilico Study

摘要

Melanoma is a type of skin cancer which is rare and most serious. It is developed due to the defect in skin pigmentation pathway associated with the major receptor called melanocortin receptor 1(MC1R). Agouti signaling protein (ASIP) on binding to MC1R induced the melanoma by producing pheomelanin. In this study, our aim is to prevent the binding of ASIP to MC1R by mutating ASIP with various amino acids computationally.The MC1R protein sequence (Q01726) was modelled using MODELLER 9.18. Mutation study was performed with SPDBV software. Protein-protein interaction was conducted with HADDOCK 2.2 server (High Ambiguity Driven DOCKing). Mutation was carried out in the active residue of ASIP-R117 with A, C, K, S based on their physiochemical property with wide variety. Docking result shows that, the parameters viz., haddock score, RMSD, electrostatic energy and z-score of MC1R-ASIP (R117A) were found to have -97.9±2.7, -9.5±0.2 A, -61.0±25.4 kcal/mol and -2.0 respectively which was higher than that of the standard values given in the literature. Whereas the mutant R117K shows RMSD (0.8±0.5 A), electrostatic energy (-193.0±25.8 kcal/mol) and z-score (-2.3) along with haddock score (-131.2±13.1)which was very low when compared with native form. Hence, the mutant MC1R-ASIP (R117A) exhibited to have poor binding affinity. Moreover, MC1R-ASIP (R117A) complex does not show any hydrogen bond interaction. Therefore, the mutant ASIP (R117A) might be the probable choice to prevent the MC1R-ASIP complex formation. However, more detailed analysis need to be carried out to have an in-depth understanding on the in vivo significance of this bi-molecular interaction.