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Plasmodium falciparum  develops resistance to artemisinin upon exposure to the anti-malarial drug. Various mutations in the  Plasmodium falciparum  Kelch13 ( Pf K13) protein such as Y493H, R539T, I543T and C580Y have been associated with anti-malarial drug resistance. These mutations impede the regular ubiquitination process that eventually invokes drug resistance. However, the relationship between the mutation and the mechanism of drug resistance has not yet been fully elucidated. The comparative protein dynamics are studied by performing the classical molecular dynamics (MD) simulations and subsequent analysis of the trajectories adopting root-mean-square fluctuations, the secondary-structure predictions and the dynamical cross-correlation matrix analysis tools. Here, we observed that the mutations in the Kelch-domain do not have any structural impact on the mutated site; however, it significantly alters the overall dynamics of the protein. The loop-region of the BTB-domain especially for Y493H and C580Y mutants is found to have the enhanced dynamical fluctuations. The enhanced fluctuations in the BTB-domain could affect the protein–protein ( Pf K13-Cullin) binding interactions in the ubiquitination process and eventually lead to anti-malarial drug resistance. Communicated by Ramaswamy H. Sarma

How do the mutations in Pf K13 protein promote anti-malarial drug resistance?