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The protonation state of the catalytic aspartates in plasmepsin II

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R. Friedman; A. Caflisch

Journal: FEBS Lett.
Year: 2007
Volume: 581
Issue: 21
Pages: 4120-4124
DOI: 10.1016/j.febslet.2007.07.033
Type of Publication: Journal Article

Animals; Aspartic Acid; Aspartic Acid Endopeptidases; Catalytic Domain; Computer Simulation; Hydrogen Bonding; Models, Molecular; Plasmodium; Protons; Protozoan Proteins; Water


Assigning the correct protonation state to the catalytic residues is essential for a realistic modelling of an enzyme's active site. Plasmepsins are pharmaceutically relevant aspartic proteases involved in haemoglobin degradation by Plasmodium spp. In aspartic proteases, one of the two catalytic aspartates is protonated, while the other is negatively charged. Here, multiple explicit-water molecular dynamics simulations of plasmepsin II, uncomplexed and with a hydroxypropylamine peptidomimetic inhibitor, indicate that protonation of Asp214 favours a stable active site structure. Moreover, the protonation state of the catalytic aspartate has a strong influence on a linear chain of hydrogen bonds with the adjacent side chains.