Year: 2026
Type: article
Abstract: Natural Diels-Alderases catalyse [4+2] cycloadditions by preorganizing substrates into reactive conformations. However, the roles of other catalytic factors, such as electrostatic effects, remain elusive. Here, we combine conceptual density functional theory (CDFT) descriptors and electric field analysis to unravel the electrostatic basis of activity in the Diels-Alderase AbyU. Previously, four different enzyme-substrate poses were identified, of which two showed catalytically favorable free energy barriers based on quantum mechanical/molecular mechanical (QM/MM) reaction simulations. Here, we show that atom-condensed Fukui functions can predict the reactivity from reactant conformations alone, focusing on the diene carbons involved in bond formation. The importance of the enzyme-diene interaction is supported by electric field analysis, which shows how reactivity of enzyme-substrate poses correlates with alignment of the enzyme field along the diene moiety. Our findings establish a basis for predicting and engineering Diels-Alderase activity based on electrostatic and electronic reactivity features.
Source: Chemical Communications
DOI: 10.1039/d5cc05141j
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: hybrid
Funders: National Science Foundation, University of Bristol, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Max-Planck-Gesellschaft, Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, Fondo Nacional de Desarrollo Científico y Tecnológico
Awards: G1916387042, G2521535780, CATPHOTO: Creating Evolvable Photocatalytic Designer Enzymes to Combat the Global Energy and Climate Crisis, G7037072674, G7895754634, Multi-scale enzyme modelling for SynBio: optimizing biocatalysts for selective synthesis of bioactive compounds, G8372834321, EPSRC and BBSRC Centre for Doctoral Training in Synthetic Biology
OpenAlex ID: W7118676896