Malaria is a major cause of global morbidity and mortality. Currently, chemotherapy remains our best choice to control the disease. However, current therapeutics and prophylactics for malaria are under massive challenge due to the emergence of drug-resistant parasites. New drugs with novel modes of action are urgently required. The Plasmodium falciparum neutral aminopeptidase, PfA-M1, is essential for the final stage of hemoglobin digestion during parasite infection and is a validated antimalarial drug target. The mechanism by which the protease enzyme loads the hemoglobin peptide substrate to its active site and then removes the free amino acid product remains unclear. To further our understanding of the mechanism of action of PfA-M1 enzyme, we are undertaking a classical all-atom Molecular Dynamics (MD) study on PfA-M1 to investigate the relevant motion. Further, we are also undertaking a Steered Molecular Dynamics (SMD) approach on (1) an inhibitor bound model of the enzyme, PfA-M1|Bestatin, and (2) a substrate bound model in order to provide testable hypotheses of possible pathways to the active site of PfA-M1. Our preliminary MD results suggest that the N-terminal Domain I of PfA-M1 undergoes a conformational change from a “closed” to “open” form of the protein. This movement appears to rely on a hinge located within the catalytic domain. These computational findings will be supported by molecular biology, enzyme assays and protein crystallography. The results from these studies will identify how peptides and inhibitors access the buried active site of the enzyme.