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On the orientation of the catalytic dyad in aspartic proteases
University of Zürich, Switzerland. (Computational Chemistry and Biochemistry (CCBG))ORCID iD: 0000-0001-8696-3104
2010 (English)In: Proteins: Structure, Function, and Bioinformatics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 78, no 6, p. 1575-1582Article in journal (Refereed) Published
Abstract [en]

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 β-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°–120°, in agreement with the perpendicular orientation in the re-refined X-ray structure. The noncoplanar arrangement is prevalent also in the β-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).

Place, publisher, year, edition, pages
2010. Vol. 78, no 6, p. 1575-1582
Keywords [en]
plasmepsin; beta-secretase; molecular dynamics; density functional theory; hiv protease; scc-dftb; m06
National Category
Theoretical Chemistry Structural Biology
Research subject
Natural Science
Identifiers
URN: urn:nbn:se:lnu:diva-14219DOI: 10.1002/prot.22674OAI: oai:DiVA.org:lnu-14219DiVA, id: diva2:445527
Available from: 2011-10-04 Created: 2011-09-16 Last updated: 2018-01-26Bibliographically approved

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Friedman, Ran

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