The present project will be focused on understanding enzyme dynamics, mechanisms and binding by applying multilevel computational methods in direct comparison to experimental studies. In addition, the conformational properties of newly purified enzymes will be explored based on structures, modelled by homology. The subjects of this study will be SAM-dependent methyltransferases; a putative bacterial methylamine dehydrogenase; and iron-containing enzymes with importance for biomedicine. This will be an exciting opportunity for a postgraduate student to achieve training in state-of-the-art computational modelling methods, respecting his/her own interests, attitudes and individual learning style. He/She will interact actively with the supervisory team and also with other scientists from the University Biomolecular and Biomedical Research Centre (BioRec). The student will learn how to apply Molecular Dynamics (MD) simulations to explore the conformational flexibility of the overall protein structure, the dynamics of the interactions between substrates, cofactors and active site residues (hydrogen bonds, electrostatic interactions and van der Waals contacts), and how they influence the reaction mechanism and binding. The next level of training will include understanding enzyme mechanisms by i) using quantum chemistry methods on a cluster formed from the most important amino acid side chains from the active site, the substrate and the cofactor; ii) using more sophisticated the Combined Quantum Mechanical and Molecular Mechanical Method (QM/MM) in order to explore the impact of the conformational dynamics, mutational effects and long-range electrostatic interactions on the enzyme mechanism. Relevant alternative mechanisms will be explored. The calculated mechanisms and activation barriers will be correlated to the experimentally measured ones. The graduate student will interact also with our external experimental collaborators in the UK, EU and USA. The postgraduate student will achieve training in building structural models of proteins using homology modelling, in combination with molecular dynamics simulations for their further refining and validating the by combination of calculated and experimental Circular Dichroism spectra.
This project will be supervised by Dr Christo Christov, Prof Iain Sutcliffe and Dr Tatyana Karabencheva but initial expressions of interest should be submitted to Dr Christo Christov, christo.christov@northumbria.ac.uk
Funding Notes:
This PhD programme is available to self-funding applicants only. Applicants should hold a first or upper second class honours degree (in a relevant subject) from a Higher Education institution, or equivalent. Students who are not UK/EU residents are eligible to apply, provided they hold the relevant academic qualifications, together with an IELTS score of at least 6.5 with no component mark of below 6.0.
References:
Christo Christov, Patricia González-Bulnes, Fanny Malhaire, Tatyana Karabencheva, Cyril Goudet, Jean-Philippe Pin, Amadeu Llebaria and Jesús Giraldo (2011), Integrated Synthetic, Pharmacological and Computational Investigation ofcis 2 (3,5 dichlorophenylcarbamoyl) cyclohexane carboxylic acid enantiomers as Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 4, ChemMedChem, 6, 1, 131-140 DOI: 10.1002/cmdc. 201000378
T Karabencheva and C. Christov , (2010), Mechanisms of Protein Circular Dichroism: Insights from Computational Modelling, Invited review article Advances in Protein Chemistry and Structural Biology, 80, 85-115
C. Christov and T. Karabencheva (2010) Computational Insight in Protein Circular Dichroism: Detailed Analysis of Contributions of Individual Chromophores in TEM-1 ß-Lactamase, Theoretical Chemistry Accounts, 151, 39-45, DOI: 10.1007/s00214-010-0744-4
C Christov, T. Karabencheva and A. Lodola (2008) Aromatic Rotational Strengths and Environmental Effects in enzymes: An Electronic Structural Study on β-Lactamases from Class A. Chemical Physics Letters 456, 89-95, doi:10.1016/j.cplett.2008.03.012
A. Lodola, M. Mol, S. Rivara, C. Christov, G. Tarzia, D. Piomelli and A. Mulholland (2008) Identification of productive inhibitor binding orientation in fatty acid amide hydrolase (FAAH) by QM/MM mechanistic modelling. Chem.Commun. 214 – 216,DOI: 10.1039/b714136j
A Soriano, R. Castillo, C. Christov, J. Andres, V. Moliner and I. Tunon (2006) Catalysis in Glycine N-Methyltransferase: Testing Electrostatic Stabilization and Compression Hypothesis, Biochemistry, 45, 14917 -14925