title: Dynamical footprint of falcipain-2 catalytic triad in hemoglobin-β-bound state.
abstract: 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.
authors.affiliation: a Department of Molecular Pharmacology and Neuroscience , Nagasaki University , Nagasaki , Japan.
authors.forename: I O
authors.initials: IO
authors.lastname: Omotuyi
authors.forename: T
authors.initials: T
authors.lastname: Hamada
mesh_terms: D001665:Binding Sites; D055162:Biocatalysis; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D006454:Hemoglobins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D056004:Molecular Dynamics Simulation; D010963:Plasmodium falciparum / Q000201:enzymology; D011485:Protein Binding; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000737:chemistry* / Q000378:metabolism; D011789:Quantum Theory; D013816:Thermodynamics
chemical_list: D006454:Hemoglobins; D015800:Protozoan Proteins; D003546:Cysteine Endopeptidases; C416224:falcipain 2
keywords: FP-2; activation energy; dihedral switch; dynamical footprint; hemoglobin-β