Research Guides

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, interleukin-4, human growth hormone, lipid transfer proteins, nitroreductase, a variety of heme binding proteins and peptide models. 

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, studies of peptide containing modified amino acid residues and modelling non-native states of proteins seen under low pH conditions and in the presence of organic solvents such as trifluoroethanol. 

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 alpha-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, 55, 15990-16010.

 Interpretation of Seemingly Contradictory Data: Low NMR S² Order Parameters Observed in Helices and High NMR S² Order Parameters in Disordered Loops of the Protein hGH at Low pH. L. J. Smith, R. Athill, W.  F. van Gunsteren and N. Hansen  Chem. Eur. J. 2017, 23, 9585-9591.

Using Complementary NMR Data Sets To Detect Inconsistencies and Model Flaws in the Structure Determination of Human Interleukin-4 L.J. Smith, W. F. van Gunsteren and N. Hansen J. Phys. Chem. B 2017, 121, 7055-7063.

Validation of molecular simulations: an overview of issues. W. F. van Gunsteren, X. Daura, N. Hansen, A. E. Mark, C. Oostenbrink, S. Riniker and L. J. Smith Angew. Chem. Int. Ed. 2018, 57, 884-902.