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In Silico Molecular Modelling and Design of Heme-Containing Peroxidases for Industrial Applications

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In Silico Molecular Modelling and Design of Heme-Containing Peroxidases for Industrial Applications In silico molecular modelling and design of heme-containing peroxidases for industrial applications Marina Cañellas Fontanilles Aquesta tesi doctoral està subjecta a la llicència Reconeixement- NoComercial 3.0. Espanya de Creative Commons. Esta tesis doctoral está sujeta a la licencia Reconocimiento - NoComercial 3.0. España de Creative Commons. This doctoral thesis is licensed under the Creative Commons Attribution-NonCommercial 3.0. Spain License. Marina Cañellas Fontanilles molecular modelling and design of heme-containing peroxidases for industrial applications applications industrial for peroxidases molecular modelling and design of heme-containing In silico In silico molecular modelling and design of heme-containing peroxidases for industrial applications Marina Cañellas Fontanilles UNIVERSITAT DE BARCELONA Facultat de Farmàcia i Ciències de l’Alimentació Programa de Doctorat en Biotecnologia In silico molecular modelling and design of heme-containing peroxidases for industrial applications Memòria presentada per Marina Cañellas Fontanilles per optar al títol de doctor per la Universitat de Barcelona Dirigida per: Dr. Victor Guallar Tasies Dr. Maria Fátima Lucas Tutora: Dr. Josefa Badia Palacín Marina Cañellas Fontanilles Barcelona, 2018 “Voici mon secret: L’essentiel est invisible pour les yeux.” “And now here is my secret: what is essential is invisible to the eye.” Antoine de Saint-Exupéry, Le Petit Prince Table of Contents ACKNOWLEDGEMENTS ............................................................................ i LIST OF PUBLICATIONS .......................................................................... iii OUTLINE OF THE THESIS ........................................................................ v ABBREVIATIONS ....................................................................................... vi CHAPTERS 1 INTRODUCTION .................................................................................... 1 1.1 ENZYMES............................................................................................. 3 1.1.1 Brief history of enzymes ........................................................... 3 1.1.2 Enzymes: the perfect catalysts .................................................. 4 1.1.3 Use of enzymes for industrial & technological applications ...... 8 1.2 SYSTEMS OF STUDY: HEME-CONTAINING PEROXIDASES ....... 10 1.2.1 Dye-decolorizing peroxidases (DyPs) ..................................... 14 1.2.2 Unspecific peroxygenases (UPOs).......................................... 15 1.3 COMPUTATIONAL ENZYME MODELLING ................................... 18 1.3.1 Overview ............................................................................... 18 1.3.2 Methods for the in silico enzyme modelling ............................ 18 1.3.2.1 Quantum Mechanics-based methods .............................................. 19 1.3.2.2 Molecular Mechanics-based methods ............................................. 22 1.3.2.3 Hybrid QM/MM methods ............................................................. 29 1.3.3 Protein-related theories ......................................................... 31 1.3.3.1 Enzyme kinetics ............................................................................ 31 1.3.3.2 Electron transfer in proteins ........................................................... 33 1.4 COMPUTATIONAL ENZYME ENGINEERING ................................ 35 1.4.1 Overview ............................................................................... 35 1.4.2 Computational de novo enzyme design ................................... 36 1.4.3 Computational enzyme redesign ............................................. 37 1.4.3.1 Rational redesign ........................................................................... 38 1.4.3.2 Semi-rational redesign ................................................................... 40 2 OBJECTIVES ......................................................................................... 43 3 RESULTS ............................................................................................... 47 3.1 REACTION MECHANISMS DESCRIPTION ..................................... 49 3.1.1 Article I .................................................................................. 51 3.1.2 Article II................................................................................. 77 3.1.3 Article III ............................................................................. 115 3.2 ENHANCED VARIANT RATIONALIZATION ................................ 129 3.2.1 Article IV ............................................................................. 131 3.2.2 Article V ............................................................................... 143 3.2.3 Article VI.............................................................................. 173 3.3 COMPUTATIONAL ENZYME REDESIGN ..................................... 205 3.3.1 Article VII ............................................................................ 206 4 RESULTS SUMMARY AND DISCUSSION ....................................... 235 4.1 REACTION MECHANISMS DESCRIPTION ................................... 237 4.1.1 Catalytic surface radical in dye-decolorizing peroxidases..... 237 4.1.2 Steroid hydroxylation by AaeUPO ........................................ 239 4.1.3 Molecular determinants for selective hydroxylation of vitamins D2 and D3 by fungal peroxygenases. ..................................... 241 4.2 ENHANCED VARIANT RATIONALIZATION ................................ 242 4.2.1 Asymmetric sulfoxidation by engineering the heme pocket of AauDyP……. ........................................................................ 242 4.2.2 Synthesis of 1-naphthol by an AaeUPO variant..................... 245 4.2.3 Selective synthesis of 5’-OHP by an evolved AaeUPO .......... 246 4.3 COMPUTATIONAL ENZYME REDESIGN ..................................... 248 4.3.1 Towards the efficient production of FDCA: Molecular modelling and in silico design of AaeUPO enzyme ................................ 248 5 CONCLUSIONS ................................................................................... 251 6 REFERENCES ..................................................................................... 255 Acknowledgements ACKNOWLEDGEMENTS To thank all the people that in one way or another have helped me in the realization of this thesis is not a trivial task. As an enzyme, this thesis is the result of a great number of small contributions that have given it the shape it has now. It is not only the binding site that matters, but also the remaining elements. That is why I will take my time to acknowledge all the people that have helped me to improve this work or have made this four-year road easier (sometimes even without noticing). Without all these tiny participations this thesis would not have been the same. This section has been written in distinct languages, in an attempt to exemplify that sci- ence does not care about frontiers. Així doncs, comencem pel principi, per qui em va obrir les portes del seu grup permetent-me realitzar aquesta tesi: en Victor Guallar i la Fátima Lucas. Moltes gràcies Victor per donar-me aquesta increïble oportunitat que m’ha fet créixer tant en l’àmbit professional com en el personal. Gràcies per guiar aquest treball cap a la feina ben feta, per tots els teus suggeriments, idees i correccions. Un especial agradecimiento a Fati. Gracias por ser mi guía durante todo este viaje, por toda la ayuda que me has brindado, por tus recomendaciones y por tus “¡sí se puede!”. Ha sido un autentico placer trabajar contigo! En segon lloc, gràcies a totes les persones que en algun moment o altre han format part del meu grup al BSC. Gràcies per tots els bons moments (i pels que encara queden!), per la ciència compartida i la feina feta, perquè amb molts de vosaltres m’he guanyat una amistat i perquè un bon ambient a la feina ho fa tot més fàcil! Especialment, mil gràcies a en Ferran, a l’Emanuele i a en Gerard, heu fet que aquest camí sigui molt més planer! També he d’agrair a aquelles persones del de- partament de Life Sciences que, tot i no ser implícitament del meu grup, també han sigut peces clau en aquest procés. Gràcies per les converses, viatges, i bons mo- ments en general, ha sigut un autèntic plaer! También tengo que agradecer a todos los colaboradores del proyecto INDOX con quien he tenido el placer de trabajar: los miembros del grupo de Ángel Martínez en el CSIC-CIB, de Miguel Alcalde en el CSIC-ICP y de Ana Guitérrez en el CSIC- IRNAS. En especial, gracias a Patricia Molina, Patricia Gómez, Dolores Linde y Esteban Babot por el increíble trabajo experimental. A la meva tutora de la tesi a la UB, Josefa Badía, i als membres de la SED de la facultat de farmàcia per tota l’ajuda que m’han proporcionat durant aquests anys. També vull agrair als responsables del projecte NOVADOMUS a la UB per a -i- Acknowledgements donar-me la increïble oportunitat de poder fer una estada d’11 mesos a la Univer- sitat d’Ottawa. A special section goes for all the people that I had the pleasure to meet and to work with while doing my Novadomus stay at Prof. Roberto Chica Lab, at the University of Ottawa. Thanks to Roberto and to all the members of The Chica Lab for treating me as one more in your group. Although the work I performed there is not directly included in this thesis, having the opportunity of learning about Computational Protein Design techniques will be of crucial importance for my professional career in the
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