Dynamical footprint of falcipain-2 catalytic triad in hemoglobin-β-bound state

• Published in: Journal of biomolecular structure & dynamics 2015-05, Vol.33 (5), p.1027-1036
• Main Authors: Omotuyi, I.O., Hamada, T.
• Format: Article
• Language: English
• Subjects: activation energy; Binding Sites; Biocatalysis; Cysteine Endopeptidases - chemistry; Cysteine Endopeptidases - metabolism; dihedral switch; dynamical footprint; FP-2; hemoglobin-β; Hemoglobins - chemistry; Hemoglobins - metabolism; Humans; Hydrolysis; Molecular Dynamics Simulation; Plasmodium; Plasmodium falciparum - enzymology; Protein Binding; Protein Folding; Protein Structure, Secondary; Protein Structure, Tertiary; Protozoan Proteins - chemistry; Protozoan Proteins - metabolism; Quantum Theory; Thermodynamics
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2014.924878

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.