The chemical understanding of biomolecular recognition in epigenetics

Projektinformationen

ChemEpigen

ID Finanzhilfevereinbarung: 715691

DOI

10.3030/715691

Projekt abgeschlossen

EK-Unterschriftsdatum 14 Dezember 2016

Startdatum 1 April 2017

Enddatum 31 März 2022

Finanziert unter

• EXCELLENT SCIENCE - European Research Council (ERC)

Gesamtkosten

€ 1 500 000,00

EU-Beitrag

€ 1 500 000,00

Koordiniert durch

SYDDANSK UNIVERSITET
Denmark

Periodic Reporting for period 4 - ChemEpigen (The chemical understanding of biomolecular recognition in epigenetics)

Berichtszeitraum: 2021-09-01 bis 2022-03-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

The molecular complexity of human life is, among others, a result of numerous posttranslational modifications of histone proteins that control the structure and function of human chromatin. Histone lysine and arginine methylations are among the most widespread posttranslational modifications and could lead to gene activation or repression. This project is aimed at providing the most comprehensive and complete understanding of biomolecular recognition between methylated histones and chromatin-associated proteins. We have applied a unique physical-organic chemistry approach that introduces the smallest controllable variations in histones and associated proteins, and thus enables to precisely test the underlying noncovalent interactions that govern biomolecular recognition in epigenetics. Our investigations have introduced novel chemical tools for detailed molecular studies of posttranslational modifications of histones in the range of short peptides, histone proteins and the nucleosome. Results from this work are important from both a fundamental molecular perspective as well as from the biomedical perspective, because proteins involved in epigenetic regulation processes are important targets for therapeutic interventions.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

This ERC project is aimed at providing the most comprehensive and complete chemical understanding of the biomolecular recognition processes in epigenetics, using the rigorous physical-organic chemistry as the main approach. Three lines of research have been explored, focusing on biomolecular recognition of methylated lysines, methylated arginines and unstructured histone tails. We have successfully carried out chemical investigations on the recognition of trimethyllysine by epigenetic proteins, by a unique integration of state-of-the-art experimental and computational approaches. Building on basic work on histone peptides, we have incorporated several trimethyllysine analogues into intact histone proteins, and used such designed histone proteins for construction of the higher order octameric histone assembly. We have also developed novel chemical methods for preparation of histones that possess a large panel of dimethylarginine analogues, and for preparation of well-defined cyclic histones. Novel chemical methods developed in this project will provide an important toolbox for future (bio)molecular studies of histones, chromatin-associated proteins, and other proteins of epigenetic importance, with the unprecedented level of molecular detail. As a response to the Covid-19 pandemic, we have successfully designed and developed potent peptides that bind to the spike protein of SARS-CoV-2, thus providing a basis for future research on anti-Covid-19 therapeutics.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

Our established research programme uniquely combines state-of-the-art experiments and computations, collectively aimed at providing the most complete understanding of biomolecular recognition of epigenetic processes. Synthetic, biostructural, thermodynamic and kinetic studies are strongly complemented by quantum chemical analyses, molecular dynamics simulations and water thermodynamics calculations. It is envisioned that such holistic approach will enable the most precise understanding of the role of noncovalent interactions and water in biomolecular recognition between histones and associated proteins. Combined with development of novel chemical tools for epigenetics research, our conceptually and methodologically innovative molecular studies will contribute to a deeper understanding of posttranslational modifications of histones and their link with chromatin structure and function.

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