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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-31638

Friedman, R; Caflisch, A (2010). On the orientation of the catalytic dyad in aspartic proteases. Proteins, 78(6):1575-1582.

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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). Proteins 2010. (c) 2010 Wiley-Liss, Inc.


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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
Dewey Decimal Classification:570 Life sciences; biology
Deposited On:19 Feb 2010 06:29
Last Modified:05 Apr 2016 13:58
Additional Information:The definitive version is available at www3.interscience.wiley.com
Publisher DOI:10.1002/prot.22674
PubMed ID:20112416

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