Dynamical footprint of falcipain-2 catalytic triad in hemoglobin-β-bound state
Falcipain-2 (FP-2) is a member of papain family of cysteine proteases and the major hemoglobinase of the hemoglobin detoxification and hemozoin polymerization complex localized in the food vacuole of the plasmodium species. FP-2 is currently gaining clinical significance as the drug target of choice in combating malaria epidemic. Here, a theoretical FP-2/hemoglobin complex has been proposed and the dynamical footprint and energetics of binding have been investigated using molecular and quantum mechanics approaches. The mapped interaction interface comprises residues 34–51 of hemoglobin and cysteine-42/histidine-174/glutamine-36/asparagine-173/204 and subsites S1, S1′, and S3 of FP-2. In hemoglobin-bound FP-2, asparagine-173 preferentially partners histidine-174, while glutamine-36 is preferred in ligand-free state. Cysteine-42 exhibits dihedral switch from 110° to 30° in free and bound states, respectively, with exclusion of water from the binding core upon hemoglobin binding. Hemoglobin similarly exhibits high occupancy within .2 nm distance with charged amido acid-rich subsites S1 and S3 of FP-2 functioning in tandem to reduce conformational flexibility of hemoglobin and facilitate the formation of a stabilizing anti-parallel β-sheet between Leucine-172-valine-176 of FP-2 and phenylalanine-45-asparate-47 of hemoglobin and to overcome the + 1.13e + 5 eV activation energy required to optimize the FP-2/hemoglobin-β conformation that precedes hydrolysis.