Mutational Analysis of Interleukin-11 and its Consequences on Cancer and COVID-19 Related Cytokine Storm -An Extensive Molecular Dynamics Study.

ABSTRACT

BACKGROUND: Interleukin-11 is a pleiotropic cytokine that is known to play an important role in the progression of various forms of cancer by modulating the survival and proliferation of tumour cells. IL11 also demonstrates a structural homology to IL6, the predominant cytokine involved in COVID-19. This makes IL11 a potential therapeutic target in both diseases. OBJECTIVE: This study aimed to evaluate the impact of the two-point mutations, R135E and R190E, on the stability of IL11 and their effect on the binding affinity of IL11 with its receptor IL11Rα. It is a molecular level analysis based on the existing experimental validation. METHODS: Computer-aided drug designing techniques, such as molecular modelling, molecular docking, and molecular dynamics simulations, were employed to determine the consequential effects of the two-point mutations. RESULTS: Our analysis revealed that the two mutations led to a decrease in the overall stability of IL11. This was evident by the increased atomic fluctuations in the mutated regions as well as the corresponding elevation in the deviations seen through RMSD and Rg values. It was also accompanied by a loss in the secondary structural organisation in the mutated proteins. Moreover, mutation R135E led to an increase in the binding affinity of IL11 with IL11Rα and the formation of a more stable complex in comparison to the wild-type protein with its receptor. CONCLUSION: Mutation R190E led to the formation of a less stable complex than the wild-type, which suggests a decrease in the binding affinity between IL11 and IL11Rα.