Insights into epigenetic modulation from computational studies

Thesis

Histone monomers are proteins found in the nucleosome, which contain tail domains that can be post-translationally modified as part of epigenetic modulation. The accumulation of these chemical groups on histone amino acid residues such as lysine, alter the flexibility of the nucleosome, influencing how transcriptional machinery binds to DNA. As a result, epigenetic regulation has large impacts on gene activation and repression, which can be exploited by cancerous cells to proliferate in hypoxic and dense tumour conditions. Subsequently, research to elucidate the chemical mechanisms driving the enzymes responsible for reading, writing, and erasing these post-translational modifications (PTMs) gained increasing attention in recent decades. In contribution to this field, the work presented here discusses the use of computational chemistry techniques, such as quantum mechanics (QM) and molecular dynamics (MD) simulations, to shed light on the underlying behaviour of the PTM substrates and epigenetic receptors. Chapter 1 will introduce the relevant protein families, computational theory, and previous pioneering work in the field. In Chapter 2, an in-depth analysis using several in silico approaches to optimise a 5-isoxazolylbenzimidazole inhibitor (Fig. 1, blue) and bromodomain cation–π interaction is discussed, followed by details of a large-scale study exploring all the available crystallographic PDB data containing an analogous interaction. Chapter 3 characterizes the enthalpic landscape of the rate-determining step for demethylation of epigenetic eraser Fe(II)-αKG substrates, such as DNA nucleobase 1-methyladenine, using a combination of ab initio and DFT calculations. Chapters 4, 5, and 6 discuss the results of work performed in collaboration with experimental groups. MD simulations are employed in Chapter 4 to understand the effects on recognition after altering trimethyllysine, the natural substrate of several epigenetic readers, by shortening and lengthening its side chain or inverting the backbone stereochemistry (Fig. 1, green). In Chapter 5, the wild type substrate is kept constant while the aromatic cage of the reader proteins is mutated and examined using MD simulations (Fig. 1, orange). A different application of modelling modified lysines is applied in Chapter 6, which discusses the results of a collaboration to understand the role of carbamyl-lysine in a novel degradation mechanism of carbapenem, an antibiotic of the last resort.

Authors: Kumar, K

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Quantum Mechanics; Epigenetics; Molecular Dynamics; DFT
• Subjects: Molecular dynamics; Chemistry, Organic; Computational chemistry; Epigenetics