QM/MM Best Practice Workshop webinar: Multiscale Simulation of Monoaminergic System: Applications to Neurodegeneration (2021-01-08)

This is the sixth webinar in the BioExcel Virtual Workshop on Best Practices in QM/MM Simulation of Biomolecular Systems.

Title: Multiscale Simulation of Monoaminergic System: Applications to Neurodegeneration

Speaker: Prof. Janez Mavri

Friday 8 January, 2021
14:00 CET



Monoamine oxidase (MAO), which exists in two isozymic forms, MAO A and MAO B, is an important flavoenzyme responsible for the metabolism of biogenic amines such as dopamine, serotonin, adrenaline and noradrenaline. In this work, we present atomic details of the rate-limiting step of dopamine degradation by MAO B, which consists of the hydride transfer from the methylene group of the substrate to the flavin moiety of the enzyme.

This contribution builds on our previous quantum chemical study of the same reaction using a cluster model [1], but now considering the full dimensionality of the hydrated enzyme. Well-converged activation free energies were calculated by employing the Empirical Valence Bond (EVB) approach of Warshel and coworkers [2].

We show that the MAO B enzyme is specifically tuned to catalyze the hydride transfer step from the substrate to the FAD prosthetic group and that it lowers the activation barrier by 12.1 kcal/mol compared to the same reaction in aqueous solution, a rate enhancement of more than 8 orders of magnitude [3]. The calculated barrier in the enzyme of 16.1 kcal/mol is in excellent agreement with the experimental value of 16.5 kcal/mol.

Path integral calculation of H/D kinetic isotope effect for MAO B will be discusssed [4]. Results for simulation of MAO A catalyzed decomposition of noradrenaline will be given [5] and the effects of MAO A point mutations on decomposition of phenylethylamine [6], adrenaline [9] and serotonin [10] will be presented. The relevance of MAO inhibition [7,9] and dopamine autoxidation [11][12] for neurodegeneration and its prevention will also be discussed.


Prof. Janez Mavri
National Institute of Chemistry and University of Ljubljana

Janez Mavri is head and scientific counselor of the Laboratory for Computational Biochemistry and Drug Design at Slovenia’s National Institute of Chemistry, and Professor of Pharmaceutical Chemistry at the University of Ljubljana.

His research interests and expertise span theoretical aspects of pharmacology – multiscale simulation of enzyme reactions, hydrogen bonding, nuclear quantum effects, transport phenomena and receptor triggering – and direct applications of computational pharmacology, including drug design and carcinogenesis. Janez has published over 100 articles and book chapters as well as organised and taught in a number of Summer and Winter Schools on these topics.

Janez has held visiting positions in research groups at the Universities of Groningen, Calgary, and Franche-Comté, been recipient of a Long Term Human Frontier Science Program Fellowship and a Fulbright Scholarship (hosted by Arieh Warshel), and lectured at a Gordon Research Conference (Isotopes in Biological and Chemical Sciences).

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[1] R. Vianello M. Repič and J.Mavri, Eur. J. Org. Chem. (2012) 7057-7065

[2] A. Warshel, Computer Modelling of Chemical Reactions in Enzymes and Solutions, J. Wiley and Sons, 1991

[3] M. Repič, R. Vianello, M. Purg, F. Duarte, P. Bauer, S.C.L. Kamerlin and J. Mavri, Empirical valence bond simulations of the hydride transfer step in the monoamine oxidase B catalyzed metabolism of dopamine, PROTEINS, 82 (2014) 3347-3355

[4] J. Mavri, R. A. Matute, Z. T. Chu, R. Vianello, Path Integral Simulation of the H/D Kinetic Isotope Effect in Monoamine Oxidase B Catalyzed Decomposition of Dopamine, J. Phys. Chem. B, 120 (2016) 3488−3492.; S.C.L. Kamerlin, J. Mavri and A. Warshel, FEBS Letters, 584 (2010) 2759-2766

[5] M. Poberžnik, M. Purg, M. Repič, J. Mavri and R. Vianello, Empirical Valence Bond Simulations of the Hydride-Transfer Step in the Monoamine Oxidase A Catalyzed Metabolism of Noradrenaline, J. Phys. Chem. B, 120 (2016) 11419−11427

[6] G. Oanca, M. Purg, J. Mavri, J.C. Shih, J. Stare, Insights into enzyme point mutation effect by molecular simulation: phenylethylamine oxidation catalyzed by monoamine oxidase A, PCCP,18 (2016) 13346-13356.

[7] M. Pavlin, M. Repič, R. Vianello and J. Mavri, The Chemistry of Neurodegeneration: Kinetic Data and Their Implications, Mol. Neurobiol. 53 (2016) 3400–3415

[8] A. Albreht, I. Vovk, J. Mavri, J. Marco-Contelles, R.R. Ramsay, Evidence for a Cyanine Link Between Propargylamine Drugs and Monoamine Oxidase Clarifies the Inactivation Mechanism, Front. Chem. 6 (2018) 169

[9] G. Oanca, J. Stare, J. Mavri, How Fast Monoamine Oxidases Decompose Adrenaline? Kinetics of Isoenzymes A and B Evaluated by Empirical Valence Bond Simulation, PROTEINS: Structure, Function, and Bioinformatics, 85 (2017) 2170-2178

[10] A. Prah, M. Purg, J. Stare, R. Vianello, J. Mavri, How Monoamine Oxidase A Decomposes Serotonin: An Empirical Valence Bond Simulation of the Reactive Step, J. Phys. Chem. B, 124 (2020) 8259−8265

[11] N. Umek, B. Geršak, N. Vintar, M. Šoštarič, J. Mavri, Dopamine Autoxidation Is Controlled by Acidic pH, Front. Mol. NeuroSci. 11 (2018) article 467, doi: 10.3389/fnmol.2018.00467

[12] D. Pregeljc, D. Teodorescu-Perijoc, R. Vianello, N. Umek, J. Mavri, How Important is the Use of Cocaine and Amphetamines in the Development of Parkinson Disease? A Computational Study, Neurotox. Res. 37 (2020) 724–73