Plasmodium falciparum (P. falciparum) is the main parasite known to cause malaria in humans. The antimalarial drug atovaquone is known to inhibit the Qo-site of the cytochrome bc1 complex of P. falciparum, which ultimately blocks ATP synthesis, leading to cell death. Through the years, mutations of the P. falciparum cytochrome bc1 complex, causing resistance to atovaquone, have emerged. The present investigation applies molecular dynamics (MD) simulations to study how the specific mutations Y279S and L282V, known to cause atovaquone resistance in malarial parasites, affect the inhibition mechanism of two known inhibitors. Binding free energy estimates were obtained through free energy perturbation calculations but were unable to confidently resolve the effects of mutations due to the great complexity of the binding environment. Meanwhile, basic mechanistic considerations from the MD simulations provide a detailed characterization of inhibitor binding modes and indicate that the Y279S mutation weakens the natural binding of the inhibitors, while no conclusive effect of the L282V mutation could be observed.
Bibliografisk noteFunding Information:
The authors are grateful for financial support from the Lundbeck Foundation, the Danish Council for Independent Research, the Volkswagen Stiftung (Lichtenberg professorship to I.A.S.), and the DFG (Grant Nos. GRK1885 and SFB1372). The authors are also grateful to the DeiC National HPC Center (SDU) for providing the computational resources necessary for the calculations.
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