Department of Biochemistry University of Oxford Department of Biochemistry
University of Oxford
South Parks Road
Oxford OX1 3QU

Tel: +44 (0)1865 613200
Fax: +44 (0)1865 613201
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Resume of Past Research

A highly multidisciplinary biophysical approach has been adopted in the study of proteins and lipids in model and natural membranes. This work has been in three productive phases, beginning with graduate work on thermodynamic studies of lipids in liposomal and model systems (Astbury Department of Biophysics, Leeds, 1972 - 1975), followed by post-doctoral research into structural and functional studies of the molecular specificity of lipid-protein in membranes (Max Plank Institute for Biophysics, Göttingen, Germany, 1976 - 1980). Since returning to an independent faculty position in Oxford (1980), new methodologies have been developed, initially around wide-line NMR (1980-2000) but then high resolution solid state NMR (1994-2009) for the study of biomolecular systems with specific application for resolving high resolution (sub-Å) structural and dynamic details of ligand- and drug-receptor interactions in the absence of other structural information (Watts, 2005, Nature Reviews Drug Discovery, 4, 555-568; invited review). During this time, most biophysical methods have been employed, and resulting publications include the use of NMR, ESR, ultracentrifugation, diffraction/scattering (X-ray, optical and neutron), differential scanning calorimetry, electron microscopy, CD, FRET, ATIR, membrane protein crystallizations, SPR, peptide synthesis and computational approaches, as well as molecular biology for expression, mutagenesis, in-gel fluorescence, PCR, fermentation, directed isotope labelling and novel membrane protein reconstitutions.  The general approach is thus to address a system in a “hypothesis driven” approach aimed at understanding biology with a range of appropriate methods, rather than specialize in one method. 

Research highlights  (1972 - 1980)
  • DMPC single bilayer vesicle characterization through the phase transition using hydrodynamics (1974-1978);
  • synthesis of >30 lipid nitroxide spin-labels (types and positional isomers) for membrane studies (1976-1980);
  • demonstration and qualification of specific lipid-protein interactions supported by functional studies (1976-1980);
  • observation and explanation of “ripple” phases in charged bilayers;
  • titration of anionic lipids and demonstration of isothermal triggering of phase behaviour (1978);
  • observation of NMR J-couplings in lipids (1979);
  • demonstration of mismatch in membranes as a site for enhanced permeability (1977-1979).
Some notable achievements since 1980:
  • characterization of a lipid-induced (using synthesized deuterated cardiolipin) "molten globule" state of a membrane associated protein, cytochrome c (1992 - 1995);
  • identification of the first lipid-anchored protein, Thy-1, and description of the lipid (saturated PE) involved (1984);
  • one of the earliest demonstrations of lipid-lipid interactions and presence of internal PE hydrogen bonding at bilayer surfaces, using non-perturbing deuterium NMR methods (1980 - 1986);
  • patenting and first use of liposomes in food flavouring and colouring;
  • identification of a direct link between lipid dynamics in bilayers and their hydration state using deuterium NMR (1992 - 1995);
  • precise and quantitative resolution of individual lipid types (cardiolipin, PE and PC) in mixed lipid bilayers using magic angle spinning 31P NMR;
  • solid state NMR study of a large integral membrane protein in a fully functional form, namely, glucose in GalP (1992-1994);
  • conformational description of a drug (ulcer treatment compound) in the ligand binding site of a fully functional, membrane bound ATPase (1996);
  • description of the conformation of retinal in ground and M412states of bacteriorhodopsin, using direct and non-perturbing deuterium solid state NMR approaches ahead of 3D crystal structures (1989-1995);
  • thermodynamic model of entropy-driven membrane protein 2D array formation in mixed lipid bilayers to complement experimental (EM) data (1998);
  • structural resolution of retinal in rhodopsin in both the dark and meta I activated form (1997-2000);
  • development of a new, high sensitivity and high resolution solid state NMR method (MAOSS) with Clemens Glaubitz (1998-2000);
  • direct observation of a neurotransmitter (neurotensin) at its target site in a GPCR (2003);
  • resolution of two models of  ß-amyloid binding to membranes (2004)
  • structural constraints determined for an integral membrane-embedded protein using solid state NMR (2005);
  • observation of 17O as a nucleus in a biological macromolecule (2005);
  • description of a P-type ATPase inhibitor and its target site by solid state NMR (2006); and,
  • complete conformation and dynamic description of acetylcholine (the largest ligand described) at its binding site in the membrane-embedded nAChR (2008).

More than 310 papers and reviews have been published, over 60% of which are in high impact journals (Nature, Nature Str. Biol., PNAS, JACS, Science, Biophysical Journal, Biochemistry, etc) and invited talks (averaging 15 per year since 1995) have been presented at most of the relevant major international meetings. H-index=55; >9900 citations, according to Google Scholar Profile.

58 graduate students have been trained in the laboratory, and over 80 post-docs have been employed at various times.

International and national recognition has been in the form of several medals, awards and named lectures.2015 Royal Society of Chemistry Interdisciplinary Prize ; 2015 Biophysical Society Anantrace Membrane Protein Award and Prize; XXV Godnev Annual Lecture and Award, National Academy of Sciences, Belarus (2014); “Frontiers in Sciences” Lecturer (2008), Texas A&M University, USA; Distinguished Professor, Kyun-won University, Seoul, Korea (2004); International Advisor, Korea Research Institute of Bioscience and Biotechnology (KRIBB) (2004 on); Hascoe Medal Lecturer, University of Connecticut, USA (2004); Royal Society of Chemistry Award for Biomembrane Chemistry for 2001; Moses Gomberg Lecturer, University of Michigan, USA (2001); Wilsmore Fellowship to the School of Chemistry, University of Melbourne, Australia (2000); The 1998 ANZMAG Lecturer; The Biochemical Society (UK) Morton Lecturer (1999); The Pfizer Lecture, University of Sheffield (1992); SERC-CNRS Maxime Hanss Prize for Biophysics (1992); Fulbright Scholarship (1987/88); 350th Commemorative Medal, Helskini University, Finland (1990).

 

 

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