Research Guides

Department of Chemistry University of Oxford

Professor L.J. Smith

My research combines experimental and theoretical approaches to probe the structural and dynamical properties of proteins, both in their native folded form and in non-native partly folded, misfolded and denatured states. The study of non-native protein conformations is challenging, as these states are often highly flexible systems in which multiple conformers are being adopted. Non-native protein conformations are of increasing interest because of their relevance to understanding protein stability, folding, misfolding and aggregation. Protein misfolding has particular importance with respect to disease states such as Alzheimer’s disease, Parkinson’s disease and bovine spongiform encephalopathy (BSE) and is also significant in our understanding of the role of proteins in food allergies.

The work particularly uses molecular dynamics simulations in combination with data from high-resolution NMR techniques. Models from the MD simulations provide a framework for interpreting experimental data while the experimental results helps prompt new theoretical developments.  Systems we are currently studying include alpha-lactalbumin, lysozyme, lipid transfer proteins, a b-type variant of cytochrome c552, mouse major urinary protein, nitroreductase, a variety of heme binding proteins and peptides composed of beta-amino acids. 


Current projects include characterising the disulphide bond shuffling seen in alpha-lactalbumin and lipid transfer proteins on prolonged heating, using MD simulations to identify how subtle sequence changes between lipid transfer proteins from different species give rise to significantly different ligand binding modes and preferences, developing methods for using order parameters from 15N relaxation studies and residual dipolar coupling constants as restraints in MD simulations, and modeling the non-native states of proteins seen under high pressure conditions and in the presence of organic solvents such as trifluoroethanol. 














The structural characteristics of non-specific lipid transfer protein explain their resistance to gastroduodenal proteolysis. R. Wijesinha-Bettoni, Y. Alexeev, P. Johnson, J. Marsh, A. I. Sancho, S. U. Abdullah, A. R. Mackie, P. R. Shewry, L. J. Smith and E. N. C. Mills Biochemistry 2010, 49, 2130-2139.

Heme proteins – diversity in structural characteristics, function and folding. L. J. Smith, A. Kahraman and J. M. Thornton  Proteins: Structure, Function and Bioinformatics 2010, 78, 2349-2368.

A systematic study of the solid state and solution phase conformational preferences of beta-peptides derived from transpentacin. E. Abraham, C. W. Bailey, T. D. W. Claridge, S. G. Davies, K. B. Ling, B. Odell, T. L. Rees, P. M. Roberts, A. J. Russell, A. D. Smith, L. J. Smith, H. R. Storr, M. J. Sweet, A. L. Thompson, J. E, Thomson, G. E. Tranter and D. J. Watkin Tetrahedron – Asymmetry 2010, 21,1797-1815.

Residual dipolar couplings: are multiple independent alignments always possible? V. A. Higman, J. Boyd, L. J. Smith and C. Redfield. J. Biomol. NMR 2011, 49, 53-60.

Cavity hydration as a gateway to unfolding: An NMR study of hen lysozyme at high pressure and low temperature. Y. O. Kamatari, L. J. Smith, C. M. Dobson and K. Akasaka Biophys. Chem. 2011, 65, 24-30.

A systematic study of the solid state and solution phase conformational preferences of beta-peptides derived from C(3)-alkyl substituted transpentacin derivatives. E. Abraham, T. D. W. Claridge, S. G. Davies, B. Odell, P. M. Roberts, A. J. Russell, A. D. Smith, L. J. Smith, H. R. Storr, M. J. Sweet, A. L. Thompson, J. E. Thomson, G. E. Tranter and D. J. Watkin Tetrahedron – Asymmetry 2011, 22, 69-100.

Ester-linked hen egg white lysozyme shows a compact fold in a molecular dynamics simulation - possible causes and sensitivity of experimentally observable quantities to structural changes maintaining this compact fold.  A. P. Eichenberger, L. J. Smith and W. F. van Gunsteren FEBS J. 2012, 279, 299-315.

Charge-state dependent compaction and dissociation of protein complexes: Insights from ion mobility and molecular dynamics.  Z. Hall, A. Politis, M. F. Bush, L. J. Smith and C. V. Robinson J. Amer. Chem. Soc. 2012, 134, 3429-3438.

Characterization of an alternative low energy fold for bovine a-lactalbumin formed by disulfide bond shuffling.  S. Lewney and L. J. Smith Proteins: Structure, Function and Bioinformatics 2012, 80, 913-919.

Probing the Structure and Dynamics of Proteins by Combining Molecular Dynamics Simulations and Experimental NMR Data. J. R. Allison, S. Hertig, J. H. Missimer, L. J. Smith, M. O. Steinmetz and J. Dolenc J. Chem. Theory and Computation 2012, 8, 3430-3444. 

Multiple binding modes for palmitate to barley lipid transfer protein facilitated by the presence of proline 12. L. J. Smith, W. F. van Gunsteren and J. R. Allison Protein Sci. 2013, 22, 56-64.

Structure of hen egg-white lysozyme solvated in TFE/water: a molecular dynamics simulation study based on NMR data. A. P. Eichenberger, W. F. van Gunsteren and L. J. Smith J. Biomol. NMR 2013, 55, 339-353.

The Dynamics of Lysozyme from Bacteriophage Lambda in Solution Probed by NMR and MD Simulations. L. J. Smith, A. M. Bowen, A. Di Paolo, A. Matagne and C. Redfield ChemBioChem. 2013, 14, 1780-1788.

Comparison of the backbone dynamics of wild-type Hydrogenobacter thermophilus cytochrome c552 and its b-type variant. K. Tozawa, S. Ferguson, C. Redfield and L. J. Smith  J. Biomol NMR 2015, 62, 221-231.

Characterization of the flexible lip regions in bacteriophage lambda lysozyme using MD simulations. L. J. Smith, W. F. van Gunsteren and N. Hansen Eur. Biophys. J.  2015, 44, 235-247.

On the use of time-averaging restraints when deriving biomolecular structure from 3J-coupling values obtained from NMR experiments.  L. J. Smith, W. F. van Gunsteren and N. Hansen J. Biomol NMR 2016, 66, 69-83.

A molecular dynamics simulation investigation of the relative stability of the cyclic peptide octreotide and its deprotonated and its (CF3)-Trp substituted analogs in different solvents. L. J. Smith, G. Rought Whitta, J. Dolenc, D. Wang, W. F. van Gunsteren  Bioorg. Med. Chem.  2016, 24, 4936-4948.

Deriving structural information from experimentally measured data on biomolecules.  W. F. van Gunsteren, J.  R. Allison, X. Daura, J. Dolenc, N. Hansen, A. E. Mark, C. Oostenbrink, V. H. Rusu, and L. J. Smith Angew. Chem. Int. Ed. 2016, in press.