title: On the orientation of the catalytic dyad in aspartic proteases.
abstract: The recent re-refinement of the X-ray structure of apo plasmepsin II from Plasmodium falciparum suggests that the two carboxylate groups in the catalytic dyad are noncoplanar, (Robbins et al., Acta Crystallogr D Biol Crystallogr 2009;65: 294-296) in remarkable contrast with the vast majority of structures of aspartic proteases. Here, evidence for the noncoplanarity of the catalytic aspartates is provided by analysis of multiple explicit water molecular dynamics (MD) simulations of plasmepsin II, human beta-secretase, and HIV-protease. In the MD runs of plasmepsin II, the angle between the planes of the two carboxylates of the catalytic dyad is almost always in the range 60 degrees -120 degrees , in agreement with the perpendicular orientation in the re-refined X-ray structure. The noncoplanar arrangement is prevalent also in the beta-secretase simulations, as well as in the runs with the inhibitor-bound proteases. Quantum-mechanics calculations provide further evidence that before catalysis the noncoplanar arrangement is favored energetically in eukaryotic aspartic proteases. Remarkably, the coplanar orientation of the catalytic dyad is observed in MD simulations of HIV-protease at 100 K but not at 300 K, which indicates that the noncoplanar arrangement is favored by conformational entropy. This finding suggests that the coplanar orientation in the crystal structures of apo aspartic proteases is promoted by the very low temperature used for data collection (usually around 100 K).
authors.affiliation: Department of Biochemistry, University of Zürich, Switzerland. r.friedman@bioc.uzh.ch
authors.forename: Ran
authors.initials: R
authors.lastname: Friedman
authors.forename: Amedeo
authors.initials: A
authors.lastname: Caflisch
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry; D001059:Apoproteins / Q000737:chemistry; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry; D057055:Aspartic Acid Proteases / Q000737:chemistry*; D055162:Biocatalysis; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D016333:HIV Protease / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011789:Quantum Theory; D013997:Time Factors
chemical_list: D001059:Apoproteins; D053829:Amyloid Precursor Protein Secretases; D057055:Aspartic Acid Proteases; D016282:Aspartic Acid Endopeptidases; D016333:HIV Protease; C089643:plasmepsin