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dc.contributor.authorPrivett, H. K.-
dc.contributor.authorKiss, G.-
dc.contributor.authorLee, T. M.-
dc.contributor.authorBlomberg, R.-
dc.contributor.authorChica, R. A.-
dc.contributor.authorThomas, L. M.-
dc.contributor.authorHilvert, D.-
dc.contributor.authorHouk, K. N.-
dc.contributor.authorMayo, S. L.-
dc.date.accessioned2018-08-27T06:45:15Z-
dc.date.available2018-08-27T06:45:15Z-
dc.date.issued2012-
dc.identifier.issn0027-8424de_CH
dc.identifier.issn1091-6490de_CH
dc.identifier.urihttps://digitalcollection.zhaw.ch/handle/11475/9664-
dc.description.abstractA general approach for the computational design of enzymes to catalyze arbitrary reactions is a goal at the forefront of the field of protein design. Recently, computationally designed enzymes have been produced for three chemical reactions through the synthesis and screening of a large number of variants. Here, we present an iterative approach that has led to the development of the most catalytically efficient computationally designed enzyme for the Kemp elimination to date. Previously established computational techniques were used to generate an initial design, HG-1, which was catalytically inactive. Analysis of HG-1 with molecular dynamics simulations (MD) and X-ray crystallography indicated that the inactivity might be due to bound waters and high flexibility of residues within the active site. This analysis guided changes to our design procedure, moved the design deeper into the interior of the protein, and resulted in an active Kemp eliminase, HG-2. The cocrystal structure of this enzyme with a transition state analog (TSA) revealed that the TSA was bound in the active site, interacted with the intended catalytic base in a catalytically relevant manner, but was flipped relative to the design model. MD analysis of HG-2 led to an additional point mutation, HG-3, that produced a further threefold improvement in activity. This iterative approach to computational enzyme design, including detailed MD and structural analysis of both active and inactive designs, promises a more complete understanding of the underlying principles of enzymatic catalysis and furthers progress toward reliably producing active enzymes.de_CH
dc.language.isoende_CH
dc.publisherNational Academy of Sciencesde_CH
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of Americade_CH
dc.rightsLicence according to publishing contractde_CH
dc.subjectAlgorithmsde_CH
dc.subjectCatalysisde_CH
dc.subjectCatalytic domainde_CH
dc.subjectComputational biologyde_CH
dc.subjectX-ray crystallographyde_CH
dc.subjectLigandsde_CH
dc.subjectChemical modelsde_CH
dc.subjectMolecular cnformationde_CH
dc.subjectMolecular dynamics simulationde_CH
dc.subjectPoint mutationde_CH
dc.subjectProtein engineeringde_CH
dc.subjectProtonsde_CH
dc.subject.ddc660.6: Biotechnologiede_CH
dc.titleIterative approach to computational enzyme designde_CH
dc.typeBeitrag in wissenschaftlicher Zeitschriftde_CH
dcterms.typeTextde_CH
zhaw.departementLife Sciences und Facility Managementde_CH
dc.identifier.doi10.1073/pnas.1118082108de_CH
dc.identifier.pmid22357762de_CH
zhaw.funding.euNode_CH
zhaw.issue10de_CH
zhaw.originated.zhawNode_CH
zhaw.pages.end3795de_CH
zhaw.pages.start3790de_CH
zhaw.publication.statuspublishedVersionde_CH
zhaw.volume109de_CH
zhaw.publication.reviewPeer review (Publikation)de_CH
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Privett, H. K., Kiss, G., Lee, T. M., Blomberg, R., Chica, R. A., Thomas, L. M., Hilvert, D., Houk, K. N., & Mayo, S. L. (2012). Iterative approach to computational enzyme design. Proceedings of the National Academy of Sciences of the United States of America, 109(10), 3790–3795. https://doi.org/10.1073/pnas.1118082108
Privett, H.K. et al. (2012) ‘Iterative approach to computational enzyme design’, Proceedings of the National Academy of Sciences of the United States of America, 109(10), pp. 3790–3795. Available at: https://doi.org/10.1073/pnas.1118082108.
H. K. Privett et al., “Iterative approach to computational enzyme design,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 10, pp. 3790–3795, 2012, doi: 10.1073/pnas.1118082108.
PRIVETT, H. K., G. KISS, T. M. LEE, R. BLOMBERG, R. A. CHICA, L. M. THOMAS, D. HILVERT, K. N. HOUK und S. L. MAYO, 2012. Iterative approach to computational enzyme design. Proceedings of the National Academy of Sciences of the United States of America. 2012. Bd. 109, Nr. 10, S. 3790–3795. DOI 10.1073/pnas.1118082108
Privett, H. K., G. Kiss, T. M. Lee, R. Blomberg, R. A. Chica, L. M. Thomas, D. Hilvert, K. N. Houk, and S. L. Mayo. 2012. “Iterative Approach to Computational Enzyme Design.” Proceedings of the National Academy of Sciences of the United States of America 109 (10): 3790–95. https://doi.org/10.1073/pnas.1118082108.
Privett, H. K., et al. “Iterative Approach to Computational Enzyme Design.” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 10, 2012, pp. 3790–95, https://doi.org/10.1073/pnas.1118082108.


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