Exploring the Development of Ground-State Destabilization and Transition-State Stabilization in Two Directed Evolution Paths of Kemp Eliminases.

ACS Catalysis
Garima JindalArieh Warshel

Abstract

Computer-aided enzyme design presents a major challenge since in most cases it has not resulted in an impressive catalytic power. The reasons for the problems with computational design include the use of nonquantitative approaches, but they may also reflect other difficulties that are not completely obvious. Thus, it is very useful to try to learn from the trend in directed evolution experiments. Here we explore the nature of the refinement of Kemp eliminases by directed evolution, trying to gain an understanding of related requirements from computational design. The observed trend in the directed evolution refinement of KE07 and HG3 are reproduced, showing that in the case of KE07 the directed evolution leads to ground-state destabilization, whereas in the case of HG3 the directed evolution leads to transition-state stabilization. The nature of the different paths of the directed evolution is examined and discussed. The present study seems to indicate that computer-aided enzyme design may require more than calculations of the effect of single mutations and should be extended to calculations of the effect of simultaneous multiple mutations (that make a few residues preorganized effectively). However, the analysis of two known e...Continue Reading

References

Nov 19, 2004·Journal of the American Chemical Society·Mats H M Olsson, Arieh Warshel
Aug 10, 2006·Chemical Reviews·Arieh WarshelMats H M Olsson
Oct 20, 2006·Biochimica Et Biophysica Acta·Arieh WarshelWilliam W Parson
Mar 21, 2008·Nature·Daniela RöthlisbergerDavid Baker
Nov 4, 2008·Journal of the American Chemical Society·Anastassia N AlexandrovaWilliam L Jorgensen
Jan 10, 2009·The Journal of Physical Chemistry. B·Anastassia N Alexandrova, William L Jorgensen
Jan 24, 2009·Biochemistry·Maite RocaArieh Warshel
Feb 21, 2009·Biotechnology Journal·Alexandra Vardi-KilshtainArieh Warshel
Dec 29, 2009·Journal of Molecular Biology·Olga KhersonskyDan S Tawfik
Feb 13, 2010·Proceedings of the National Academy of Sciences of the United States of America·Shina C L KamerlinArieh Warshel
Sep 11, 2010·Proceedings of the National Academy of Sciences of the United States of America·Maria P FrushichevaArieh Warshel
Feb 1, 2011·Journal of Molecular Biology·Olga KhersonskyDan S Tawfik
Apr 13, 2011·Proceedings of the National Academy of Sciences of the United States of America·Ivan V KorendovychWilliam F DeGrado
Aug 13, 2011·Proceedings of the National Academy of Sciences of the United States of America·Andrew J AdamczykArieh Warshel
Feb 24, 2012·Proceedings of the National Academy of Sciences of the United States of America·Heidi K PrivettStephen L Mayo
Jun 12, 2012·Proceedings of the National Academy of Sciences of the United States of America·Olga KhersonskyDan S Tawfik
Mar 19, 2013·Current Opinion in Chemical Biology·Hajo KriesDonald Hilvert
Mar 26, 2013·Angewandte Chemie·Gert KissK N Houk
May 8, 2013·The FEBS Journal·Hein J Wijma, Dick B Janssen
Oct 18, 2013·Nature·Rebecca BlombergDonald Hilvert
May 13, 2014·Current Opinion in Chemical Biology·Maria P FrushichevaArieh Warshel
Mar 26, 2015·Proceedings of the National Academy of Sciences of the United States of America·Patrick SchopfArieh Warshel
Jul 5, 2016·Physical Chemistry Chemical Physics : PCCP·Asmit BhowmickTeresa Head-Gordon

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Citations

Oct 4, 2018·Physical Chemistry Chemical Physics : PCCP·Maite RocaVicent Moliner
Dec 17, 2019·Chemphyschem : a European Journal of Chemical Physics and Physical Chemistry·Carles Acosta-SilvaAntoni Oliva
Dec 28, 2018·Proceedings of the National Academy of Sciences of the United States of America·Garima JindalArieh Warshel
Aug 25, 2020·Chemical Science·Valeria A RissoShina C L Kamerlin
Feb 1, 2021·Current Opinion in Structural Biology·H Adrian BunzelAdrian J Mulholland
Feb 18, 2020·Current Opinion in Structural Biology·Dénes BertaEdina Rosta
Jun 5, 2020·Journal of the American Chemical Society·Rory M CreanShina C L Kamerlin
Aug 21, 2021·Nature Chemistry·H Adrian BunzelAdrian J Mulholland
Apr 14, 2020·Journal of Chemical Theory and Computation·Wiktor Beker, W Andrzej Sokalski
Jun 22, 2017·The Journal of Physical Chemistry. B·Garima JindalArieh Warshel
Nov 13, 2020·Journal of the American Chemical Society·Michal BilerShina Caroline Lynn Kamerlin

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