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  Pervasive cooperative mutational effects on multiple catalytic enzyme traits emerge via long-range conformational dynamics

Acevedo-Rocha, C. G., Li, A., D'Amore, L., Hoebenreich, S., Sanchis, J., Lubrano, P., et al. (2021). Pervasive cooperative mutational effects on multiple catalytic enzyme traits emerge via long-range conformational dynamics. Nature Communications, 12(1): 1621. doi:10.1038/s41467-021-21833-w.

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 Creators:
Acevedo-Rocha, Carlos G.1, Author
Li, Aitao2, Author
D'Amore, Lorenzo3, Author
Hoebenreich, Sabrina4, Author
Sanchis, Joaquin5, Author
Lubrano, Paul1, Author
Ferla, Matteo P.6, Author
Garcia-Borràs, Marc3, Author
Osuna, Sílvia 3, 7, Author
Reetz, Manfred T.4, 8, 9, Author              
Affiliations:
1Biosyntia ApS, Copenhagen, Denmark, ou_persistent22              
2State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, School of Life Sciences, Hubei University, Wuhan, P. R. China, ou_persistent22              
3Institut de Química Computacional i Catàlisi and Departament de Química, Universitat de Girona, Girona, Spain, ou_persistent22              
4Department of Chemistry, Philipps-University Marburg, Marburg, Germany, ou_persistent22              
5Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia, ou_persistent22              
6Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK, ou_persistent22              
7ICREA, Barcelona, Spain, ou_persistent22              
8Research Department Reetz, Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1445588              
9Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, P. R. China, ou_persistent22              

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 Abstract: Multidimensional fitness landscapes provide insights into the molecular basis of laboratory and natural evolution. To date, such efforts usually focus on limited protein families and a single enzyme trait, with little concern about the relationship between protein epistasis and conformational dynamics. Here, we report a multiparametric fitness landscape for a cytochrome P450 monooxygenase that was engineered for the regio- and stereoselective hydroxylation of a steroid. We develop a computational program to automatically quantify non-additive effects among all possible mutational pathways, finding pervasive cooperative signs and magnitude epistasis on multiple catalytic traits. By using quantum mechanics and molecular dynamics simulations, we show that these effects are modulated by long-range interactions in loops, helices and β-strands that gate the substrate access channel allowing for optimal catalysis. Our work highlights the importance of conformational dynamics on epistasis in an enzyme involved in secondary metabolism and offers insights for engineering P450s.

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Language(s): eng - English
 Dates: 2020-06-252021-01-292021-03-12
 Publication Status: Published online
 Pages: 13
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s41467-021-21833-w
 Degree: -

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Title: Nature Communications
  Abbreviation : Nat. Commun.
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 12 (1) Sequence Number: 1621 Start / End Page: - Identifier: ISSN: 2041-1723
CoNE: https://pure.mpg.de/cone/journals/resource/2041-1723