The protonation state of the catalytic aspartates in plasmepsin II.
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.
Friedman
Ran
R
Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. r.friedman@bioc.uzh.ch
Caflisch
Amedeo
A
D000818:Animals; D001224:Aspartic Acid / Q000737:chemistry*; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry*; D020134:Catalytic Domain; D003198:Computer Simulation; D006860:Hydrogen Bonding; D008958:Models, Molecular; D010961:Plasmodium / Q000201:enzymology*; D011522:Protons; D015800:Protozoan Proteins; D014867:Water / Q000737:chemistry
D011522:Protons; D015800:Protozoan Proteins; D014867:Water; D001224:Aspartic Acid; D016282:Aspartic Acid Endopeptidases; C100637:plasmepsin II