Structural and Functional Impact of the G340S Mutation in Plasmodium falciparum Ferredoxin NADP⁺ Reductase: In silico Analysis and Molecular Docking
Abstract
Plasmodium falciparum, the deadliest malaria parasite, continues to burden health systems across sub-Saharan Africa, where artemether-lumefantrine remains a frontline treatment. Partial artemisinin resistance is emerging, increasing selection pressure on lumefantrine (LM), yet the molecular basis of reduced LM susceptibility remains poorly defined. While LM has been described as refractory to resistance, its efficacy could be compromised if resistance arises. To explore candidate determinants of LM response and guided by a Gly332Ser substitution previously identified in Ferredoxin NADP + reductase from LM-selected Plasmodium berghei, we investigated the homologous G340S variant in Plasmodium falciparum ferredoxin NADP + reductase ( PfFNR), a central enzyme of the apicoplast redox system. To predict the structural and functional impact of the G340S substitution, this study integrated sequence conservation analysis, AlphaFold 3 structural modelling, structural superimposition, molecular dynamics simulation, NADPH and NADP + docking, HADDOCK docking with P. falciparum ferredoxin ( PfFd), and comparative docking of lumefantrine, primaquine, artemisinin and dihydroartemisinin. Gly340 was conserved across the Plasmodium FNR orthologs examined and mapped to a constrained loop adjacent to the NADP + binding region. Structural superimposition showed that G340S preserved the global PfFNR fold but introduced localized changes near residue 340. Exploratory single-trajectory molecular…
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