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| Protein Structure and Function: Computational Studies Using Bioinformatics, Cheminformatics and Computational Chemistry | |||||||||||||
We use computational methods to address one of the major challenges in the biomolecular sciences – understanding the relationship between protein structure and function. Such systems are complex, typically involving thousands of atoms, yet the highly specific, non-covalent manner in which molecules interact is essential for many important biological processes. By studying a variety of different systems, my research gives valuable insight into the molecular basis for a number of biological processes – catalysis, ion transport, hydrogen transfer and electron transfer. A range of bioinformatics, cheminformatics and computational chemistry techniques are used to spearhead hypothesis-driven interdisciplinary studies as part of a computer modelling/experimental verification cycle. The techniques used include: protein sequence analysis, production of three-dimensional structures using (mainly) homology modelling and molecular dynamics; studying protein-ligand complexes using binding site characterisation, pharmacophore generation, docking and molecular dynamics; studying reactions using quantum mechanical and combined quantum mechanical/molecular mechanical techniques. Additional insight is obtained using interactive molecular graphics. Current projects include: * Hydrogen tunnelling in enzymes[1,2] – for which we are spearheading a major paradigm shift away from transition state theory; * Interprotein electron transfer[3] – important in metabolism; * Cytochrome P450-substrate interactions[4] – important in drug design; * Structure-function relationships in ion channels[5] – giving insight into adverse drug interactions and control of cellular excitability. 1) Masgrau L, Roujeinikova A, Johannissen LO, Hothi P, Basran J, Ranaghan KE, Mulholland AJ, Sutcliffe MJ, Scrutton NS, Leys D (2006) “ Atomic description of an enzyme reaction dominated by proton tunneling ” Science 312 , 237-241. 2) Masgrau L, Ranaghan KE, Scrutton NS, Mulholland AJ, Sutcliffe MJ. (2007) “Tunneling and classical paths for proton transfer in an enzyme reaction dominated by tunneling: oxidation of tryptamine by aromatic amine dehydrogenase” J. Phys. Chem. B111 , 3032-3047. 3) Leys, D, Basran, J, Talfournier, F, Sutcliffe, MJ, Scrutton , NS (2003) “Extensive conformational sampling in a ternary electron transfer complex” Nat. Struct. Biol. 10 , 219-225. 4) Marechal JD, Yu J, Brown S, Kapelioukh I, Rankin EM, Wolf CR, Roberts GC, Paine MJ, Sutcliffe MJ (2006) “In silico and in vitro screening for inhibition of cytochrome P450 CYP3A4 by comedications commonly used by patients with cancer” Drug Metab. Dispos. 34 , 534-538. 5) Stansfeld PJ, Gedeck P, Gosling M, Cox B, Mitcheson JS, Sutcliffe MJ (2007) “Drug block of the hERG potassium channel: Insight from modeling” Proteins , in press. |
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