Artemisinin and its derivatives are the most effective and widely used treatment for Plasmodium falciparum malaria. The emergence and spread of drug resistance in the malaria parasite is a severe public health concern all over the malaria-endemic countries. Artemisinin resistance is defined as delayed parasite clearance following treatment with artemisinin monotherapy or with artemisinin-based combination therapy. Early signs of delayed response to artemisinin in Plasmodium falciparum parasite were first reported in 2009 in northwest Cambodia. This phenotype has been now reported in Thailand, Vietnam, Myanmar, and China. Resistance to artemisinin has also been reported in India, and is highly suspected in South America 16 and East Africa. Single site mutations in the Plasmodium falciparum Kelch13 protein (PfK13) were associated with the artemisinin resistance. Till now, 124 different non-synonymous kelch mutations have been identified which are associated with the artemisinin resistance. The frequent and most prevalent mutations detected in resistant populations are Y493H (tyrosine(Y) @493 is replaced by histidine(H)), R539T (arginine(R) @539 is replaced by threonine(T)), I543T (isoleucine(I) @543 is replaced by threonine(T)) and C580Y (cysteine(C) @580 is replaced by tyrosine(Y)) respectively. The C580Y mutation occurs in about 55% of samples with any resistance mutation in Southeast Asia and is assumed to be one of the strong molecular markers for artemisinin resistance. The next most prevalent mutation is Y493H, which occurs in about 10% of samples with any resistance mutation in Southeast-Asia. The PfK13 protein contains 726 amino-acid residues consisting of non-conserved apicomplexaspecific N-terminal region (amino-acids 1-211), highly conserved coiled-coil-containing domain (amino-acids 212-341), well-conserved BTB-domain (amino-acids 350-442) and Cterminal Kelch-domain (amino-acids 443-726) as shown in Fig. . The Kelch-domain (propeller domain) has six kelch motifs and the mutations are present in this propeller domain (Fig. ). The BTB-domain interacts with cullin protein and gets involved in protein-protein interactions. However, the Kelch domain acts as a receptor for substrate proteins to be ubiquitinated. Kelch Propeller Domain The proposed mechanism of artemisinin resistance is the proteostatic dysregulation of Plasmodium falciparum Phosphatidylinositol-3-Kinases (PfPI3K) enzyme. By binding to PfPI3K enzymes, PfK13 leads to its ubiquitination and degradation. Mutation in the PfK13 prevents this interaction, thus increasing the levels of PfPI3K enzyme and its product phosphatidylinositol 3-phosphate, subsequently leading to artemisinin resistance. A large number of PfK13 mutations have been associated with artemisinin resistance, however, it is not yet known why do these specific mutations instigate drug resistance. In this work, we have investigated the structural dynamics of PfK13 wild-type (WT) and four mutant protein structures by adopting the classical molecular dynamic simulations to address the issue and established a correlation of the protein dynamics with the artemisinin drug resistance.