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Article ; Online: Approaching the catalytic mechanism of protein lysine methyltransferases by biochemical and simulation techniques.

Schnee, Philipp / Pleiss, Jürgen / Jeltsch, Albert

Critical reviews in biochemistry and molecular biology

2024 , Page(s) 1–49

Abstract: Protein lysine methyltransferases (PKMTs) transfer up to three methyl groups to the side chains of lysine residues in proteins and fulfill important regulatory functions by controlling protein stability, localization and protein/protein interactions. The ...

Abstract	Protein lysine methyltransferases (PKMTs) transfer up to three methyl groups to the side chains of lysine residues in proteins and fulfill important regulatory functions by controlling protein stability, localization and protein/protein interactions. The methylation reactions are highly regulated, and aberrant methylation of proteins is associated with several types of diseases including neurologic disorders, cardiovascular diseases, and various types of cancer. This review describes novel insights into the catalytic machinery of various PKMTs achieved by the combined application of biochemical experiments and simulation approaches during the last years, focusing on clinically relevant and well-studied enzymes of this group like DOT1L, SMYD1-3, SET7/9, G9a/GLP, SETD2, SUV420H2, NSD1/2, different MLLs and EZH2. Biochemical experiments have unraveled many mechanistic features of PKMTs concerning their substrate and product specificity, processivity and the effects of somatic mutations observed in PKMTs in cancer cells. Structural data additionally provided information about the substrate recognition, enzyme-substrate complex formation, and allowed for simulations of the substrate peptide interaction and mechanism of PKMTs with atomistic resolution by molecular dynamics and hybrid quantum mechanics/molecular mechanics methods. These simulation technologies uncovered important mechanistic details of the PKMT reaction mechanism including the processes responsible for the deprotonation of the target lysine residue, essential conformational changes of the PKMT upon substrate binding, but also rationalized regulatory principles like PKMT autoinhibition. Further developments are discussed that could bring us closer to a mechanistic understanding of catalysis of this important class of enzymes in the near future. The results described here illustrate the power of the investigation of enzyme mechanisms by the combined application of biochemical experiments and simulation technologies.
Language	English
Publishing date	2024-03-07
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1000977-2
ISSN	1549-7798 ; 1381-3455 ; 1040-9238
ISSN (online)	1549-7798
ISSN	1381-3455 ; 1040-9238
DOI	10.1080/10409238.2024.2318547
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Article ; Online: Bayesian estimation reveals that reproducible models in Systems Biology get more citations.

Höpfl, Sebastian / Pleiss, Jürgen / Radde, Nicole E

Scientific reports

2023 Volume 13, Issue 1, Page(s) 2695

Abstract: The Systems Biology community has taken numerous actions to develop data and modeling standards towards FAIR data and model handling. Nevertheless, the debate about incentives and rewards for individual researchers to make their results reproducible is ... ...

Abstract	The Systems Biology community has taken numerous actions to develop data and modeling standards towards FAIR data and model handling. Nevertheless, the debate about incentives and rewards for individual researchers to make their results reproducible is ongoing. Here, we pose the specific question of whether reproducible models have a higher impact in terms of citations. Therefore, we statistically analyze 328 published models recently classified by Tiwari et al. based on their reproducibility. For hypothesis testing, we use a flexible Bayesian approach that provides complete distributional information for all quantities of interest and can handle outliers. The results show that in the period from 2013, i.e., 10 years after the introduction of SBML, to 2020, the group of reproducible models is significantly more cited than the non-reproducible group. We show that differences in journal impact factors do not explain this effect and that this effect increases with additional standardization of data and error model integration via PEtab. Overall, our statistical analysis demonstrates the long-term merits of reproducible modeling for the individual researcher in terms of citations. Moreover, it provides evidence for the increased use of reproducible models in the scientific community.
MeSH term(s)	Bayes Theorem ; Reproducibility of Results ; Systems Biology ; Journal Impact Factor ; Publications
Language	English
Publishing date	2023-02-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-29340-2
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Article ; Online: Thermodynamic Activity-Based Progress Curve Analysis in Enzyme Kinetics.

Pleiss, Jürgen

Trends in biotechnology

2017 Volume 36, Issue 3, Page(s) 234–238

Abstract: Macrokinetic Michaelis-Menten models based on thermodynamic activity provide insights into enzyme kinetics because they separate substrate-enzyme from substrate-solvent interactions. Kinetic parameters are estimated from experimental progress curves of ... ...

Abstract	Macrokinetic Michaelis-Menten models based on thermodynamic activity provide insights into enzyme kinetics because they separate substrate-enzyme from substrate-solvent interactions. Kinetic parameters are estimated from experimental progress curves of enzyme-catalyzed reactions. Three pitfalls are discussed: deviations between thermodynamic and concentration-based models, product effects on the substrate activity coefficient, and product inhibition.
MeSH term(s)	Binding Sites ; Biocatalysis ; Enzymes/chemistry ; Hydrophobic and Hydrophilic Interactions ; Kinetics ; Models, Theoretical ; Solvents/metabolism ; Thermodynamics ; Water
Chemical Substances	Enzymes ; Solvents ; Water (059QF0KO0R)
Language	English
Publishing date	2017-11-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	47474-5
ISSN	1879-3096 ; 0167-7799
ISSN (online)	1879-3096
ISSN	0167-7799
DOI	10.1016/j.tibtech.2017.10.004
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Article ; Online: Thermodynamic Activity-Based Interpretation of Enzyme Kinetics.

Pleiss, Jürgen

Trends in biotechnology

2017 Volume 35, Issue 5, Page(s) 379–382

Abstract: The experimentally determined Michaelis constant ... ...

Abstract	The experimentally determined Michaelis constant K
Language	English
Publishing date	2017-05
Publishing country	England
Document type	Journal Article
ZDB-ID	47474-5
ISSN	1879-3096 ; 0167-7799
ISSN (online)	1879-3096
ISSN	0167-7799
DOI	10.1016/j.tibtech.2017.01.003
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Article ; Online: Simulation Foundry: Automated and F.A.I.R. Molecular Modeling.

Gygli, Gudrun / Pleiss, Juergen

Journal of chemical information and modeling

2020 Volume 60, Issue 4, Page(s) 1922–1927

Abstract: The Simulation Foundry (SF) is a modular workflow for the automated creation of molecular modeling (MM) data. MM allows for the reliable prediction of the microscopic and macroscopic properties of multicomponent systems from first principles. The SF ... ...

Abstract	The Simulation Foundry (SF) is a modular workflow for the automated creation of molecular modeling (MM) data. MM allows for the reliable prediction of the microscopic and macroscopic properties of multicomponent systems from first principles. The SF makes MM repeatable, replicable, and findable, accessible, interoperable, and reusable (F.A.I.R.). The SF uses a standardized data structure and file naming convention, allowing for replication on different supercomputers and re-entrancy. We focus on keeping the SF simple by basing it on scripting languages that are widely used by the MM community (bash, Python) and making it reusable and re-editable. The SF was developed to assist expert users in performing parameter studies of multicomponent systems by high throughput molecular dynamics simulations. The usability of the SF is demonstrated by simulations of thermophysical properties of binary mixtures. A standardized data exchange format enables the integration of simulated data with data from experiments. The SF also provides a complete documentation of how the results were obtained, thus assigning provenance. Increasing computational power facilitates the intensification of the simulation process and requires automation and modularity. The SF provides a community platform on which to integrate new methods and create data that is reproducible and transparent (https://fairdomhub.org/studies/639/snapshots/1, https://fairdomhub.org/studies/639/snapshots/2).
MeSH term(s)	Automation ; Molecular Dynamics Simulation ; Software ; Workflow
Language	English
Publishing date	2020-04-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	190019-5
ISSN	1549-960X ; 0095-2338
ISSN (online)	1549-960X
ISSN	0095-2338
DOI	10.1021/acs.jcim.0c00018
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Article: FAIR and scalable management of small-angle X-ray scattering data.

Giess, Torsten / Itzigehl, Selina / Range, Jan / Schömig, Richard / Bruckner, Johanna R / Pleiss, Jürgen

Journal of applied crystallography

2023 Volume 56, Issue Pt 2, Page(s) 565–575

Abstract: A modular research data management toolbox based on the programming language Python, the widely used computing ... ...

Abstract	A modular research data management toolbox based on the programming language Python, the widely used computing platform
Language	English
Publishing date	2023-03-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	2020879-0
ISSN	1600-5767 ; 0021-8898
ISSN (online)	1600-5767
ISSN	0021-8898
DOI	10.1107/S1600576723001577
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Article ; Online: Molecular Mechanism of Methanol Inhibition in CALB-Catalyzed Alcoholysis: Analyzing Molecular Dynamics Simulations by a Markov State Model.

Carvalho, Henrique F / Ferrario, Valerio / Pleiss, Jürgen

Journal of chemical theory and computation

2021 Volume 17, Issue 10, Page(s) 6570–6582

Abstract: Lipases are widely used enzymes that catalyze hydrolysis and alcoholysis of fatty acid esters. At high concentrations of small alcohols such as methanol or ethanol, many lipases are inhibited by the substrate. The molecular basis of the inhibition ... ...

Abstract	Lipases are widely used enzymes that catalyze hydrolysis and alcoholysis of fatty acid esters. At high concentrations of small alcohols such as methanol or ethanol, many lipases are inhibited by the substrate. The molecular basis of the inhibition of
MeSH term(s)	Catalysis ; Ethanol/chemistry ; Fungal Proteins/antagonists & inhibitors ; Fungal Proteins/chemistry ; Lipase/antagonists & inhibitors ; Lipase/chemistry ; Methanol ; Molecular Dynamics Simulation
Chemical Substances	Fungal Proteins ; Ethanol (3K9958V90M) ; Lipase (EC 3.1.1.3) ; lipase B, Candida antarctica (EC 3.1.1.3) ; Methanol (Y4S76JWI15)
Language	English
Publishing date	2021-09-08
Publishing country	United States
Document type	Journal Article
ISSN	1549-9626
ISSN (online)	1549-9626
DOI	10.1021/acs.jctc.1c00559
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Article: Preferential Self-interaction of DNA Methyltransferase DNMT3A Subunits Containing the R882H Cancer Mutation Leads to Dominant Changes of Flanking Sequence Preferences

Mack, Alexandra / Emperle, Max / Schnee, Philipp / Adam, Sabrina / Pleiss, Jürgen / Bashtrykov, Pavel / Jeltsch, Albert

Journal of molecular biology. 2022 Apr. 15, v. 434, no. 7

2022

Abstract: Somatic R882H DNMT3A mutations occur frequently in AML, but their pathogenic mechanism is unclear. As R882H mutations usually are heterozygous, wildtype (WT) and R882H subunits co-exist in affected cells. R882 is located in the RD interface of DNMT3A ... ...

Abstract	Somatic R882H DNMT3A mutations occur frequently in AML, but their pathogenic mechanism is unclear. As R882H mutations usually are heterozygous, wildtype (WT) and R882H subunits co-exist in affected cells. R882 is located in the RD interface of DNMT3A tetramers, which forms the DNA binding site. R882H causes strong changes in the flanking sequence preferences of DNMT3A. Here, we analyzed flanking sequence preferences for CGNNNN sites showing that most disfavored sites are methylated 4–5 fold slower by R882H than WT, while it methylates most preferred sites 2-fold faster. Overall, R882H was more active than WT at 13% and less active at 52% of all CGNNNN sites. We prepared mixed DNMT3A heterotetramers containing WT and R882H subunits and show that mixed complexes preferentially assemble with an R882H/R882H RD interface. Structural comparisons and MD simulations confirmed the conclusion that the R882H RD interface is more stable than that of WT, in part because H882 forms an inter-subunit contact in the RD interface, while R882 contacts the DNA. As the subunits at the RD interface contribute the two active centers to the DNMT3A tetramer, R882H characteristic flanking sequence preferences of DNMT3A were observed in mixed tetrameric complexes containing WT and R882H subunits, and they are not diluted by the “averaged” effects of mixed or WT interfaces. Hence, R882H has a dominant effect on the flanking sequence preferences and other catalytic properties of DNMT3A in samples containing WT and R882H subunits, which may explain its pathogenic effect in heterozygous state.
Keywords	DNA ; DNA methyltransferase ; heterozygosity ; methylation ; molecular biology ; mutation
Language	English
Dates of publication	2022-0415
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2022.167482
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Article ; Online: Simulation of protein diffusion: a sensitive probe of protein-solvent interactions.

Ferrario, Valerio / Pleiss, Jürgen

Journal of biomolecular structure & dynamics

2018 Volume 37, Issue 6, Page(s) 1534–1544

Abstract: Aqueous solutions of Candida antarctica lipase B (CALB) were simulated considering three different water models (SPC/E, TIP3P, TIP4P) by a series of molecular dynamics (MD) simulations of three different box sizes (L = 9, 14, and 19 nm) to determine the ... ...

Abstract	Aqueous solutions of Candida antarctica lipase B (CALB) were simulated considering three different water models (SPC/E, TIP3P, TIP4P) by a series of molecular dynamics (MD) simulations of three different box sizes (L = 9, 14, and 19 nm) to determine the diffusion coefficient, the water viscosity and the protein density. The protein-water systems were equilibrated for 500 ns, followed by 100 ns production runs which were analysed. The diffusional properties of CALB were characterized by the Stokes radius (R
MeSH term(s)	Algorithms ; Diffusion ; Fungal Proteins/chemistry ; Hydrogen Bonding ; Lipase/chemistry ; Models, Theoretical ; Molecular Dynamics Simulation ; Proteins/chemistry ; Solvents/chemistry ; Structure-Activity Relationship ; Viscosity ; Water/chemistry
Chemical Substances	Fungal Proteins ; Proteins ; Solvents ; Water (059QF0KO0R) ; Lipase (EC 3.1.1.3) ; lipase B, Candida antarctica (EC 3.1.1.3)
Language	English
Publishing date	2018-04-24
Publishing country	England
Document type	Journal Article
ZDB-ID	49157-3
ISSN	1538-0254 ; 0739-1102
ISSN (online)	1538-0254
ISSN	0739-1102
DOI	10.1080/07391102.2018.1461689
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Article ; Online: Meta-analysis of viscosity of aqueous deep eutectic solvents and their components.

Gygli, Gudrun / Xu, Xinmeng / Pleiss, Jürgen

Scientific reports

2020 Volume 10, Issue 1, Page(s) 21395

Abstract: Deep eutectic solvents (DES) formed by quaternary ammonium salts and hydrogen bond donors are a promising green alternative to organic solvents. Their high viscosity at ambient temperatures can limit biocatalytic applications and therefore requires fine- ... ...

Abstract	Deep eutectic solvents (DES) formed by quaternary ammonium salts and hydrogen bond donors are a promising green alternative to organic solvents. Their high viscosity at ambient temperatures can limit biocatalytic applications and therefore requires fine-tuning by adjusting water content and temperature. Here, we performed a meta-analysis of the impact of water content and temperature on the viscosities of four deep eutectic solvents (glyceline, reline, N,N-diethylethanol ammonium chloride-glycerol, N,N-diethylethanol ammonium chloride-ethylene glycol), their components (choline chloride, urea, glycerol, ethylene glycol), methanol, and pure water. We analyzed the viscosity data by an automated workflow, using Arrhenius and Vogel-Fulcher-Tammann-Hesse models. The consistency and completeness of experimental data and metadata was used as an essential criterion of data quality. We found that viscosities were reported for different temperature ranges, half the time without specifying a method of desiccation, and in almost half of the reports without specifying experimental errors. We found that the viscosity of the pure components varied widely, but that all aqueous mixtures (except for reline) have similar excess activation energy of viscous flow [Formula: see text]= 3-5 kJ/mol, whereas reline had a negative excess activation energy ([Formula: see text]= - 19 kJ/mol). The data and workflows used are accessible at https://doi.org/10.15490/FAIRDOMHUB.1.STUDY.767.1 .
Language	English
Publishing date	2020-12-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-78101-y
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