Computational analysis of aspartic protease plasmepsin II complexed with EH58 inhibitor: a QM/MM MD study

Plasmepsin (PM) II is one of four enzymes in the food vacuole of Plasmodium falciparum. It has become an attractive target for combating malaria through research regarding its importance in the P. falciparum metabolism and life cycle, making it the target of choice for structure-based drug design. This paper reports the results of hybrid quantum mechanics / molecular mechanics (QM/MM) molecular dynamics (MD) simulations employed to study the details of the interactions established between PM II and N-(3-{(2-benzo[1, 3]dioxol-5-yl-ethyl)[3-(1-methyl-3-oxo-1,3-dihydro-isoindol-2-yl) propionyl]-amino}-1-benzyl-2-(hydroxyl-propyl)-4-benzyloxy-3,5dimethoxy-benzamide (EH58), a well-known potent inhibitor for this enzyme. Electrostatic binding free energy and energy terms decomposition have been computed for PM II complexed with the EH58 inhibitor. The results reveal that there is a strong interaction between Asp34, Val78, Ser79, Tyr192 and Asp214 residues and the EH58 inhibitor. In addition, we have computed the potential of the mean force (PMF) profile in order to assign the protonation state of the two catalytic aspartates in PM II-EH58 complex. The results indicate that the protonation of Asp214 favors a stable active site structure, which is consistent with our electrostatic binding free energy calculation and with previous published works.