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Amrein, Beat Anton
Alternative names
Publications (8 of 8) Show all publications
Amrein, B. A., Runthala, A. & Kamerlin, S. C. L. (2018). In Silico-Directed Evolution Using CADEE. In: T. Tobias Sikosek (Ed.), Computational Methods in Protein Evolution: (pp. 381-415). Springer Science+Business Media, LLC, part of Springer Nature
Open this publication in new window or tab >>In Silico-Directed Evolution Using CADEE
2018 (English)In: Computational Methods in Protein Evolution / [ed] T. Tobias Sikosek, Springer Science+Business Media, LLC, part of Springer Nature , 2018, p. 381-415Chapter in book (Other academic)
Place, publisher, year, edition, pages
Springer Science+Business Media, LLC, part of Springer Nature, 2018
Series
Methods in Molecular Biology, ISSN 1064-3745
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:uu:diva-368461 (URN)10.1007/978-1-4939-8736-8 (DOI)978-1-4939-8736-8 (ISBN)978-1-4939-8735-1 (ISBN)
Available from: 2018-12-04 Created: 2018-12-04 Last updated: 2019-04-04Bibliographically approved
Bauer, P., Barrozo, A., Purg, M., Amrein, B. A., Esguerra, M., Wilson, P. B., . . . Kamerlin, S. C. L. (2018). Q6: A comprehensive toolkit for empirical valence bond and related free energy calculations. SoftwareX, 388-395
Open this publication in new window or tab >>Q6: A comprehensive toolkit for empirical valence bond and related free energy calculations
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2018 (English)In: SoftwareX, ISSN 2352-7110, p. 388-395Article in journal (Refereed) Published
Abstract [en]

Atomistic simulations have become one of the main approaches to study the chemistry and dynamicsof biomolecular systems in solution. Chemical modelling is a powerful way to understand biochemistry,with a number of different programs available to perform specialized calculations. We present here Q6, anew version of the Q software package, which is a generalized package for empirical valence bond, linearinteraction energy, and other free energy calculations. In addition to general technical improvements, Q6extends the reach of the EVB implementation to fast approximations of quantum effects, extended solventdescriptions and quick estimation of the contributions of individual residues to changes in the activationfree energy of reactions.

National Category
Software Engineering
Identifiers
urn:nbn:se:uu:diva-360517 (URN)10.1016/j.softx.2017.12.001 (DOI)000457139300064 ()
Funder
Swedish Research Council, 2014-3688Swedish Research Council, 2014-2118Swedish Research Council, 2015-04928
Available from: 2018-09-14 Created: 2018-09-14 Last updated: 2019-02-25Bibliographically approved
Amrein, B. A., Steffen-Munsberg, F., Szeler, I., Purg, M., Kulkarni, Y. & Kamerlin, S. C. (2017). CADEE: Computer-Aided Directed Evolution of Enzymes. IUCrJ, 4(1), 50-64
Open this publication in new window or tab >>CADEE: Computer-Aided Directed Evolution of Enzymes
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2017 (English)In: IUCrJ, ISSN 0972-6918, E-ISSN 2052-2525, Vol. 4, no 1, p. 50-64Article in journal (Refereed) Published
Abstract [en]

The tremendous interest in enzymes as biocatalysts has led to extensive work in enzyme engineering, as well as associated methodology development. Here, a new framework for computer-aided directed evolution of enzymes (CADEE) is presented which allows a drastic reduction in the time necessary to prepare and analyze in silico semi-automated directed evolution of enzymes. A pedagogical example of the application of CADEE to a real biological system is also presented in order to illustrate the CADEE workflow.

Keywords
computational directed evolution, computational enzyme design, distributed computing, empirical valence bond, triosephosphate isomerase
National Category
Structural Biology Bioinformatics (Computational Biology) Theoretical Chemistry
Identifiers
urn:nbn:se:uu:diva-314218 (URN)10.1107/S2052252516018017 (DOI)000392925800007 ()
Funder
EU, FP7, Seventh Framework Programme, 306474Knut and Alice Wallenberg FoundationThe Royal Swedish Academy of SciencesSwedish Research Council, 2015-04928Swedish National Infrastructure for Computing (SNIC), 2015/16-12
Available from: 2017-01-31 Created: 2017-01-31 Last updated: 2018-01-13Bibliographically approved
Bauer, P., Janfalk Carlsson, Å., Amrein, B. A., Dobritzsch, D., Widersten, M. & Kamerlin, S. C. (2016). Conformational Diversity and Enantioconvergence in Potato Epoxide Hydrolase 1. Organic and biomolecular chemistry, 14(24), 5639-5651
Open this publication in new window or tab >>Conformational Diversity and Enantioconvergence in Potato Epoxide Hydrolase 1
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2016 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 14, no 24, p. 5639-5651Article in journal (Refereed) Published
Abstract [en]

Potato epoxide hydrolase 1 (StEH1) is a biocatalytically important enzyme that exhibits rich enantio-and regioselectivity in the hydrolysis of chiral epoxide substrates. In particular, StEH1 has been demonstrated to enantioconvergently hydrolyze racemic mixes of styrene oxide (SO) to yield (R)-1-phenylethanediol. This work combines computational, crystallographic and biochemical analyses to understand both the origins of the enantioconvergent behavior of the wild-type enzyme, as well as shifts in activities and substrate binding preferences in an engineered StEH1 variant, R-C1B1, which contains four active site substitutions (W106L, L109Y, V141K and I155V). Our calculations are able to reproduce both the enantio-and regioselectivities of StEH1, and demonstrate a clear link between different substrate binding modes and the corresponding selectivity, with the preferred binding modes being shifted between the wild-type enzyme and the R-C1B1 variant. Additionally, we demonstrate that the observed changes in selectivity and the corresponding enantioconvergent behavior are due to a combination of steric and electrostatic effects that modulate both the accessibility of the different carbon atoms to the nucleophilic side chain of D105, as well as the interactions between the substrate and protein amino acid side chains and active site water molecules. Being able to computationally predict such subtle effects for different substrate enantiomers, as well as to understand their origin and how they are affected by mutations, is an important advance towards the computational design of improved biocatalysts for enantioselective synthesis.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-282015 (URN)10.1039/C6OB00060F (DOI)000378933400042 ()27049844 (PubMedID)
Funder
Swedish National Infrastructure for Computing (SNIC), 25/2-10EU, European Research Council, 306474;283570Swedish Research Council, 621-2011-6055Carl Tryggers foundation , CTS13:104
Available from: 2016-04-01 Created: 2016-04-01 Last updated: 2017-11-30Bibliographically approved
Amrein, B. A., Bauer, P., Duarte, F., Janfalk Carlsson, Å., Naworyta, A., Mowbray, S. L., . . . Kamerlin, S. C. L. (2015). Expanding the catalytic triad in epoxide hydrolases and related enzymes. ACS Catalysis, 5(10), 5702-5713
Open this publication in new window or tab >>Expanding the catalytic triad in epoxide hydrolases and related enzymes
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2015 (English)In: ACS Catalysis, ISSN 2155-5435, E-ISSN 2155-5435, Vol. 5, no 10, p. 5702-5713Article in journal (Refereed) Published
Abstract [en]

Potato epoxide hydrolase 1 exhibits rich enantio- and regioselectivity in the hydrolysis of a broadrange of substrates. The enzyme can be engineered to increase the yield of optically pureproducts, as a result of changes in both enantio- and regioselectivity. It is thus highly attractive inbiocatalysis, particularly for the generation of enantiopure fine chemicals and pharmaceuticals.The present work aims to establish the principles underlying the activity and selectivity of theenzyme through a combined computational, structural, and kinetic study, using the substratetrans-stilbene oxide as a model system. Extensive empirical valence bond simulations have beenperformed on the wild-type enzyme together with several experimentally characterized mutants.We are able to computationally reproduce the differences in activities between differentstereoisomers of the substrate, and the effects of mutations in several active-site residues. Inaddition, our results indicate the involvement of a previously neglected residue, H104, which iselectrostatically linked to the general base, H300. We find that this residue, which is highlyconserved in epoxide hydrolases and related hydrolytic enzymes, needs to be in its protonatedform in order to provide charge balance in an otherwise negatively-charged active site. Our datashow that unless the active-site charge balance is correctly treated in simulations, it is notpossible to generate a physically meaningful model for the enzyme that can accurately reproduceactivity and selectivity trends. We also expand our understanding of other catalytic residues,demonstrating in particular the role of a non-canonical residue, E35, as a “backup-base” in theabsence of H300. Our results provide a detailed view of the main factors driving catalysis andregioselectivity in this enzyme, and identify targets for subsequent enzyme design efforts.

National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:uu:diva-260232 (URN)10.1021/acscatal.5b01639 (DOI)000362391500006 ()
Funder
EU, FP7, Seventh Framework Programme, 306474Swedish Research Council, 621-2011-6055, 621-2010-5145Swedish National Infrastructure for Computing (SNIC), 2015/16-12
Available from: 2015-08-18 Created: 2015-08-18 Last updated: 2017-12-04Bibliographically approved
Duarte, F., Amrein, B. A., Blaha-Nelson, D. & Kamerlin, S. C. (2015). Recent advances in QM/MM free energy calculations using reference potentials. Biochimica et Biophysica Acta - General Subjects, 1850(5), 954-965
Open this publication in new window or tab >>Recent advances in QM/MM free energy calculations using reference potentials
2015 (English)In: Biochimica et Biophysica Acta - General Subjects, ISSN 0304-4165, E-ISSN 1872-8006, Vol. 1850, no 5, p. 954-965Article, review/survey (Refereed) Published
Abstract [en]

Background: Recent years have seen enormous progress in the development of methods for modeling (bio)molecular systems. This has allowed for the simulation of ever larger and more complex systems. However, as such complexity increases, the requirements needed for these models to be accurate and physically meaningful become more and more difficult to fulfill. The use of simplified models to describe complex biological systems has long been shown to be an effective way to overcome some of the limitations associated with this computational cost in a rational way. Scope of review: Hybrid QM/MM approaches have rapidly become one of the most popular computational tools for studying chemical reactivity in biomolecular systems. However, the high cost involved in performing high-level QM calculations has limited the applicability of these approaches when calculating free energies of chemical processes. In this review, we present some of the advances in using reference potentials and mean field approximations to accelerate high-level QM/MM calculations. We present illustrative applications of these approaches and discuss challenges and future perspectives for the field. Major conclusions: The use of physically-based simplifications has shown to effectively reduce the cost of high-level QM/MM calculations. In particular, lower-level reference potentials enable one to reduce the cost of expensive free energy calculations, thus expanding the scope of problems that can be addressed. General significance: As was already demonstrated 40 years ago, the usage of simplified models still allows one to obtain cutting edge results with substantially reduced computational cost. This article is part of a Special Issue entitled Recent developments of molecular dynamics.

Keywords
Multiscale modeling, QM/MM free energy calculation, Averaging potential, Reference potential, Mean field approximation
National Category
Biophysics Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-251670 (URN)10.1016/j.bbagen.2014.07.008 (DOI)000350706700011 ()
Available from: 2015-04-24 Created: 2015-04-23 Last updated: 2017-12-04Bibliographically approved
Duarte, F., Bauer, P., Barrozo, A., Amrein, B. A., Purg, M., Åqvist, J. & Kamerlin, S. C. (2014). Force Field Independent Metal Parameters Using a Nonbonded Dummy Model. Journal of Physical Chemistry B, 118(16), 4351-4362
Open this publication in new window or tab >>Force Field Independent Metal Parameters Using a Nonbonded Dummy Model
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2014 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 118, no 16, p. 4351-4362Article in journal (Refereed) Published
Abstract [en]

The cationic dummy atom approach provides a powerful nonbonded description for a range of alkaline-earth and transition-metal centers, capturing both structural and electrostatic effects. In this work we refine existing literature parameters for octahedrally coordinated Mn2+, Zn2+, Mg2+, and Ca2+, as well as providing new parameters for Ni2+, Co2+, and Fe2+. In all the cases, we are able to reproduce both M2+-O distances and experimental solvation free energies, which has not been achieved to date for transition metals using any other model. The parameters have also been tested using two different water models and show consistent performance. Therefore, our parameters are easily transferable to any force field that describes nonbonded interactions using Coulomb and Lennard-Jones potentials. Finally, we demonstrate the stability of our parameters in both the human and Escherichia coli variants of the enzyme glyoxalase 1 as showcase systems, as both enzymes are active with a range of transition metals. The parameters presented in this work provide a valuable resource for the molecular simulation community, as they extend the range of metal ions that can be studied using classical approaches, while also providing a starting point for subsequent parametrization of new metal centers.

National Category
Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-225523 (URN)10.1021/jp501737x (DOI)000335113600010 ()
Funder
Swedish National Infrastructure for Computing (SNIC), 2013/26-1
Available from: 2014-06-23 Created: 2014-06-04 Last updated: 2018-12-03Bibliographically approved
Duarte, F., Amrein, B. A. & Kamerlin, L. (2013). Modeling catalytic promiscuity in the alkaline phosphatase superfamily. Physical Chemistry, Chemical Physics - PCCP, 15(27), 11160-11177
Open this publication in new window or tab >>Modeling catalytic promiscuity in the alkaline phosphatase superfamily
2013 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 15, no 27, p. 11160-11177Article in journal (Refereed) Published
Abstract [en]

In recent years, it has become increasingly clear that promiscuity plays a key role in the evolution of new enzyme function. This finding has helped to elucidate fundamental aspects of molecular evolution. While there has been extensive experimental work on enzyme promiscuity, computational modeling of the chemical details of such promiscuity has traditionally fallen behind the advances in experimental studies, not least due to the nearly prohibitive computational cost involved in examining multiple substrates with multiple potential mechanisms and binding modes in atomic detail with a reasonable degree of accuracy. However, recent advances in both computational methodologies and power have allowed us to reach a stage in the field where we can start to overcome this problem, and molecular simulations can now provide accurate and efficient descriptions of complex biological systems with substantially less computational cost. This has led to significant advances in our understanding of enzyme function and evolution in a broader sense. Here, we will discuss currently available computational approaches that can allow us to probe the underlying molecular basis for enzyme specificity and selectivity, discussing the inherent strengths and weaknesses of each approach. As a case study, we will discuss recent computational work on different members of the alkaline phosphatase superfamily (AP) using a range of different approaches, showing the complementary insights they have provided. We have selected this particular superfamily, as it poses a number of significant challenges for theory, ranging from the complexity of the actual reaction mechanisms involved to the reliable modeling of the catalytic metal centers, as well as the very large system sizes. We will demonstrate that, through current advances in methodologies, computational tools can provide significant insight into the molecular basis for catalytic promiscuity, and, therefore, in turn, the mechanisms of protein functional evolution.

National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:uu:diva-202285 (URN)10.1039/C3CP51179K (DOI)000320557600001 ()
Funder
EU, European Research Council, 306474Swedish Research Council, 2010-5026
Available from: 2013-06-22 Created: 2013-06-22 Last updated: 2017-12-06Bibliographically approved
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