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@ARTICLE{Petrovi:858920,
author = {Petrović, Dušan and Bokel, Ansgar and Allan, Matthew and
Urlacher, Vlada B. and Strodel, Birgit},
title = {{S}imulation-{G}uided {D}esign of {C}ytochrome {P}450 for
{C}hemo- and {R}egioselective {M}acrocyclic {O}xidation},
journal = {Journal of chemical information and modeling},
volume = {58},
number = {4},
issn = {1549-960X},
address = {Washington, DC},
publisher = {American Chemical Society64160},
reportid = {FZJ-2018-07756},
pages = {848 - 858},
year = {2018},
abstract = {Engineering high chemo-, regio-, and stereoselectivity is a
prerequisite for enzyme usage in organic synthesis.
Cytochromes P450 can oxidize a broad range of substrates,
including macrocycles, which are becoming popular scaffolds
for therapeutic agents. However, a large conformational
space explored by macrocycles not only reduces the
selectivity of oxidation but also impairs computational
enzyme design strategies based on docking and molecular
dynamics (MD) simulations. We present a novel design
workflow that uses enhanced-sampling Hamiltonian replica
exchange (HREX) MD and focuses on quantifying the substrate
binding for suggesting the mutations to be made. This
computational approach is applied to P450 BM3 with the aim
to shift regioselectively toward one of the numerous
possible positions during β-cembrenediol oxidation. The
predictions are experimentally tested and the resulting
product distributions validate our design strategy, as
single mutations led up to 5-fold regioselectivity
increases. We thus conclude that the HREX-MD-based workflow
is a promising tool for the identification of positions for
mutagenesis aiming at P450 enzymes with improved
regioselectivity.},
cin = {ICS-6 / JARA-HPC},
ddc = {540},
cid = {I:(DE-Juel1)ICS-6-20110106 / $I:(DE-82)080012_20140620$},
pnm = {551 - Functional Macromolecules and Complexes (POF3-551) /
Computational Enzyme Design $(jics69_20151101)$},
pid = {G:(DE-HGF)POF3-551 / $G:(DE-Juel1)jics69_20151101$},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:29522682},
UT = {WOS:000431088000009},
doi = {10.1021/acs.jcim.8b00043},
url = {https://juser.fz-juelich.de/record/858920},
}