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

Carlos G. Acevedo-Rocha, Aitao Li, Lorenzo D’Amore, Sabrina Hoebenreich, Joaquin Sanchis, Paul Lubrano, Matteo P. Ferla, Marc Garcia-Borràs, Sílvia Osuna () and Manfred T. Reetz ()
Additional contact information
Carlos G. Acevedo-Rocha: Biosyntia ApS
Aitao Li: Hubei University
Lorenzo D’Amore: Universitat de Girona
Sabrina Hoebenreich: Philipps-University Marburg
Joaquin Sanchis: Monash Institute of Pharmaceutical Sciences, Monash University
Paul Lubrano: Biosyntia ApS
Matteo P. Ferla: University of Oxford
Marc Garcia-Borràs: Universitat de Girona
Sílvia Osuna: Universitat de Girona
Manfred T. Reetz: Philipps-University Marburg

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-021-21833-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21833-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-21833-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().