The Quest for Accurate Theoretical
Models of Metalloenzymes: An Aid
to Experiment
Matthew G. Quesne and Sam P. de Visser
Abstract Enzymes are versatile oxidants in Nature that catalyze a range of reactions
very efficiently. Experimental studies on the mechanism of enzymes are sometimes
difficult due to the short lifetime of catalytic cycle intermediates. Theoretical modeling can assist and guide experiment and elucidate mechanisms for fast reaction
pathways. Two key computational approaches are in the literature, namely quantum
mechanics/molecular mechanics (QM/MM) on complete enzyme structures and QM
cluster models on active site structures only. These two approaches are reviewed here.
We give examples where the QM cluster approach worked well and, for instance,
enabled the bioengineering of an enzyme to change its functionality. In addition,
several examples are given, where QM cluster models were insufficient and full
QM/MM structures were needed to establish regio-, chemo-, and stereoselectivities.
1 Introduction
Metalloenzymes are extremely diverse and ubiquitous family of biocatalysts that
use earth abundant and often redox-active metal co-factors to vastly increase their
turnover frequencies [1–4]. However, the development of accurate models for such
catalysts has proven particularly challenging; owing to both the difficulties involved
in the realistic treatment of transition metals and the complex three-dimensional
structures of these large catalysts. It was not until the addition of generalized gradient approximations to density functional theory (DFT) methods in the 1990s [5]
that the study of these types of catalysts really came of age and many examples
started being reported of studies of enzymatic reaction mechanisms [6–9]. During the
M. G. Quesne (B)
School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, UK
e-mail: quesnem@cardiff.ac.uk
S. P. de Visser
The Manchester Institute of Biotechnology and School of Chemical Engineering and Analytical
Science, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK
e-mail: sam.devisser@manchester.ac.uk
© Springer Nature Switzerland AG 2019
E. Broclawik et al. (eds.), Transition Metals in Coordination Environments,
Challenges and Advances in Computational Chemistry and Physics 29,
https://doi.org/10.1007/978-3-030-11714-6_14
439
Models of Metalloenzymes: An Aid
to Experiment
Matthew G. Quesne and Sam P. de Visser
Abstract Enzymes are versatile oxidants in Nature that catalyze a range of reactions
very efficiently. Experimental studies on the mechanism of enzymes are sometimes
difficult due to the short lifetime of catalytic cycle intermediates. Theoretical modeling can assist and guide experiment and elucidate mechanisms for fast reaction
pathways. Two key computational approaches are in the literature, namely quantum
mechanics/molecular mechanics (QM/MM) on complete enzyme structures and QM
cluster models on active site structures only. These two approaches are reviewed here.
We give examples where the QM cluster approach worked well and, for instance,
enabled the bioengineering of an enzyme to change its functionality. In addition,
several examples are given, where QM cluster models were insufficient and full
QM/MM structures were needed to establish regio-, chemo-, and stereoselectivities.
1 Introduction
Metalloenzymes are extremely diverse and ubiquitous family of biocatalysts that
use earth abundant and often redox-active metal co-factors to vastly increase their
turnover frequencies [1–4]. However, the development of accurate models for such
catalysts has proven particularly challenging; owing to both the difficulties involved
in the realistic treatment of transition metals and the complex three-dimensional
structures of these large catalysts. It was not until the addition of generalized gradient approximations to density functional theory (DFT) methods in the 1990s [5]
that the study of these types of catalysts really came of age and many examples
started being reported of studies of enzymatic reaction mechanisms [6–9]. During the
M. G. Quesne (B)
School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, UK
e-mail: quesnem@cardiff.ac.uk
S. P. de Visser
The Manchester Institute of Biotechnology and School of Chemical Engineering and Analytical
Science, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK
e-mail: sam.devisser@manchester.ac.uk
© Springer Nature Switzerland AG 2019
E. Broclawik et al. (eds.), Transition Metals in Coordination Environments,
Challenges and Advances in Computational Chemistry and Physics 29,
https://doi.org/10.1007/978-3-030-11714-6_14
439