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Epoxide Hydrolase Conformational Heterogeneity for the Resolution of Bulky Pharmacologically Relevant Epoxide Substrates
Author(s) -
SerranoHervás Eila,
Casadevall Guillem,
GarciaBorràs Marc,
Feixas Ferran,
Osuna Sílvia
Publication year - 2018
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201801068
Subject(s) - epoxide , epoxide hydrolase , stereochemistry , resolution (logic) , chemistry , epoxide hydrolase 2 , combinatorial chemistry , biochemistry , enzyme , computer science , catalysis , artificial intelligence , microsome
The conformational landscape of Bacillus megaterium epoxide hydrolase ( Bm EH) and how it is altered by mutations that confer the enzyme the ability to accept bulky epoxide substrates has been investigated. Extensive molecular dynamics (MD) simulations coupled to active site volume calculations have unveiled relevant features of the enzyme conformational dynamics and function. Our long‐timescale MD simulations identify key conformational states not previously observed by means of X‐ray crystallography and short MD simulations that present the loop containing one of the catalytic residues, Asp239, in a wide‐open conformation, which is likely involved in the binding of the epoxide substrate. Introduction of mutations M145S and F128A dramatically alters the conformational landscape of the enzyme. These singly mutated variants can accept bulky epoxide substrates due to the disorder induced by mutation in the α‐helix containing the catalytic Tyr144 and some parts of the lid domain. These changes impact the enzyme active site, which is substantially wider and more complementary to the bulky pharmacologically relevant epoxide substrates.