B.Sc. (Bristol) Ph.D. (Bristol) Senior Research Fellow in Biochemistry Email R.Sessions@bris.ac.uk Internal 12145 External 0117 3312145 Room C62, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD

Research interests

Molecular Modelling

Molecular modelling is a very useful tool in the design and interpretation of experiments. This is well recognised in Bristol, where most research groups have used this technique, to a greater or lesser extent. Molecular modelling can also be thought of as a subset of Bioinformatics and, as we pass into the "post-genomic sequence era", this field will play an ever more important role in scientific research. Computer hardware advances continue to follow Moore’s law, formulated in the 1960s, which states that machine speed’s roughly double every 18 months. This is allowing the application of evermore sophisticated modelling techniques to routine problems. The following molecular modelling techniques and projects are actively pursued in this department: homology modelling; ligand/drug design; mutant design; molecular mechanics/dynamics; semi-empirical molecular orbital calculations; protein structure prediction.

Predicted Hinge bending in PGK

These two projects provide an excellent opportunity to acquire computational and programming skills in a biological environment.

Ab initio

The prediction of the three dimensional structure of a protein from its sequence alone is one of the great biological/biophysical challenges today. We have made some significant progress in this area over the last few years, and are now able to predict the structures of peptides up to 40 residues long with a fair degree of accuracy. The current folding model uses a simplified representation of protein geometry, a hydrophobicity based force field, and a genetic algorithm based search procedure. This project will be in close collaboration with Prof. A.R. Clarke.

Threading

While homology modelling is an excellent technique for structure prediction when the unknown proteins sequence is > 30% identical with the sequence of a known structure, there are many examples of sequences with no discernable homology adopting the same fold. Threading approaches this problem by attempting to match a given sequence with representative examples of all known protein folds. We will explore the use of physico-chemical potentials, derived from the ab initio folding project, in the context of threading.

Molecular Dynamics: Prion and CD2 proteins

Molecular Dynamics simulations of medium sized proteins in solvent for nanosecond periods can now be routinely obtained. This project will involve running such MD simulations on the Human Prion protein and a variety of disulphide bonded mutant CD2 proteins and comparing the results with experimental NMR protection factors measured by Dr. J. Waltho’s group in Sheffield. Thermal unfolding simulations will also be carried out to understand these processes at the atomic level. This project will be in close collaboration with Prof. A.R. Clarke This project provides an excellent opportunity to learn state-of-the art modelling techniques. Some development of analysis software involved if desired.
 

Engineering: Novel amino-transferase activities

Amino transferases are extremely useful proteins for the production of enantiomerically pure, non-natural a -amino acids. Such compounds find applications in pharmaceutical synthesis. We have had success in this area, and this project will build on that work. Some kinetics of mutants involved. This project provides an excellent opportunity to acquire PCR based protein engineering and purification skills. Some molecular modelling will be involved in the design of mutants.

2005

Forsyth JL, Beaudoin F, Halford NG, Sessions RB, Clarke AR, Shewry PR Design, expression and characterisation of lysine-rich forms of the barley seed protein CI-2
Biochimica Et Biophysica Acta-Proteins And Proteomics 1747(2) 221-227 (2005) [HTML] [PDF]

Conners R, Schambach F, Read J, Cameron A, Sessions RB, Vivas L, Easton A, Croft SL, Brady RL Mapping the binding site for gossypol-like inhibitors of Plasmodium falciparum lactate dehydrogenase.
Mol Biochem Parasitol. 142(2) 137-48 (2005) [HTML] [PDF]

Thomas GL, Sessions RB, Parker MJ. Density guided importance sampling: application to a reduced model of protein folding.
Bioinformatics 21(12) 2839-43 (2005) [HTML] [PDF]

2004

Sessions RB, Thomas GL, Parker MJ. Water as a conformational editor in protein folding.
J Mol Biol. 343(4) 1125-33 (2004) [HTML] [PDF]

Witchel HJ, Dempsey CE, Sessions RB, Perry M, Milnes JT, Hancox JC, Mitcheson JS. The low-potency, voltage-dependent HERG blocker propafenone--molecular determinants and drug trapping.
Mol Pharmacol. 66(5) 1201-12 (2004) [HTML] [PDF]

Karaguler NG, Sessions RB, Moreton KM, Clarke AR, Holbrook JJ Estimating the energetic contribution of hydrogen bonding to the stability of Candida methylica formate dehydrogenase by using double mutant cycle
Biotech. Lett. 26 (14): 1137-1140 Jul 2004 [PDF]

Cameron A, Read J, Tranter R, Winter VJ, Sessions RB, Brady RL, Vivas L, Easton A, Kendrick H, Croft SL, Barros D, Lavandera JL, Martin JJ, Risco F, Garcia-Ochoa S, Gamo FJ, Sanz L, Leon L, Ruiz JR, Gabarro R, Mallo A, de las Heras FG Identification and activity of a series of azole-based compounds with lactate dehydrogenase-directed anti-malarial activity
J. Biol. Chem. 279 (30): 31429-31439 Jul 2004 [HTML] [PDF]

Turgut-Balik D, Akbulut E, Shoemark DK, Celik V, Moreton KM, Sessions RB, Holbrook JJ, Brady RL Cloning, sequence and expression of the lactate dehydrogenase gene from the human malaria parasite, Plasmodium vivax
Biotech. Lett. 26 (13): 1051-1055 Jul 2004 [PDF]

Cliff MJ, Higgins LD, Sessions RB, et al. Beyond the EX1 limit: Probing the structure of high-energy states in protein unfolding
J. Mol. Biol. 336 (2): 497-508 Feb 13 2004 [PDF]

2003

Winter VJ, Cameron A, Tranter R, Sessions RB, Brady RL Crystal structure of Plasmodium berghei lactate dehydrogenase indicates the unique structural differences of these enzymes are shared across the Plasmodium genus
Mol. Biochem. Parasit. 131 (1): 1-10 Sep 2003 [HTML]   [PDF]

Banbury DN, Oakley JD, Sessions RB, Banting G. Tyrphostin A23 inhibits internalization of the transferrin receptor by perturbing the interaction between tyrosine motifs and the medium chain subunit of the AP-2 adaptor complex
J. Biol. Chem. 278 (14): 12022-12028 Apr 4 2003 [HTML]   [PDF]

2002

Jody M. Mason, Nicholas Gibbs, Richard B. Sessions, and Anthony R. Clarke The influence of intramolecular bridges on the dynamics of a protein folding reaction
Biochemistry 41 (40): 12093-12099 Oct 8 2002 [HTML]   [PDF]

Ciani B, Hutchinson EG, Sessions RB, Woolfson DN. A designed system for assessing how sequence affects alpha to beta conformational transitions in proteins
J. Biol. Chem. 277 (12): 10150-10155 Mar 22 2002 [HTML]   [PDF]

Alexander LG, Sessions RB, Clarke AR, Tatham AS, Shewry PR, Napier JA. Characterization and modelling of the hydrophobic domain of a sunflower oleosin
Planta 214 (4): 546-551 Feb 2002 [HTML]   [PDF]

Naylor RL, Robertson AG, Allen SJ, Sessions RB, Clarke AR, Mason GG, Burston JJ, Tyler SJ, Wilcock GK, Dawbarn D. A discrete domain of the human TrkB receptor defines the binding sites for BDNF and NT-4
Biochem. Bioph. Res CO 291 (3): 501-507 Mar 1 2002 [HTML]   [PDF] [HTML]   [PDF]

2001

Luckett S, Sessions RB, Michaelson L, et al. Amino acid sequence and molecular modelling of a lipid transfer protein from sunflower (Helianthus annus L.) seeds
Protein Peptide Lett. 8 (4): 241-248 Aug 2001

Townley HE, Sessions RB, Clarke AR, Dafforn TR, Griffiths WT. Protochlorophyllide oxidoreductase: A homology model examined by site-directed mutagenesis
Proteins 44 (3): 329-335 Aug 15 2001 [HTML]   [PDF]

Turgut-Balik D, Shoemark DK, Moreton KM, et al. Over-production of lactate dehydrogenase from Plasmodium falciparum opens a route to new antimalarials
Biotechnol. Lett. 23 (11): 917-921 Jun 2001

Turgut-Balik D, Shoemark DK, Sessions RB, et al. Mutagenic exploration of the active site of lactate dehydrogenase from Plasmodium falciparum
Biotechnol. Lett. 23 (11): 923-927 Jun 2001

Read JA, Winter VJ, Eszes CM, et al. Structural basis for altered activity of M- and H-isozyme forms of human lactate dehydrogenase
Proteins 43 (2): 175-185 May 1 2001 [HTML]   [PDF]

Gibbs N, Clarke AR, Sessions RB Ab initio protein structure prediction using physicochemical potentials and a simplified off-lattice model
Proteins 43 (2): 186-202 May 1 2001 [HTML]   [PDF]

Wakeham MC, Sessions RB, Jones MR, et al. Is there a conserved interaction between cardiolipin and the type II bacterial reaction center?
Biophys. J. 80 (3): 1395-1405 Mar 2001

Gul-Karaguler N, Sessions RB, Holbrook JJ Role of glutamate-52 in the mechanism of L-lactate dehydrogenase from Bacillus stearothermophilus
Biotechnol. Lett. 23 (5): 395-399 Mar 2001

Gul-Karaguler N, Sessions RB, Clarke AR, et al. A single mutation in the NAD-specific formate dehydrogenase from Candida methylica allows the enzyme to use NADP
Biotechnol. Lett. 23 (4): 283-287 Feb 2001

2000

Poso D, Sessions RB, Lorch M, et al. Progressive stabilization of intermediate and transition states in protein folding reactions by introducing surface hydrophobic residues
J. Biol. Chem. 275 (46): 35723-35726 Nov 17 2000 [HTML]   [PDF]

Dempsey CE, Sessions RB, Lamble NV, Campbell SJ. The asparagine-stabilized beta-turn of apamin: Contribution to structural stability from dynamics simulation and amide hydrogen exchange analysis
Biochemistry 39 (51): 15944-15952 Dec 26 2000 [HTML]   [PDF]

Mark Lorch, Jody M. Mason, Richard B. Sessions, and Anthony R. Clarke Effects of mutations on the thermodynamics of a protein folding reaction: Implications for the mechanism of formation of the intermediate and transition states
Biochemistry 39 (12): 3480-3485 Mar 28 2000 [HTML]   [PDF]

Pandya MJ, Sessions RB, Williams PB, Dempsey CE, Tatham AS, Shewry PR, Clarke AR. Structural characterization of a methionine-rich, emulsifying protein from sunflower seed
Proteins 38 (3): 341-349 Feb 15 2000 [HTML]   [PDF]

1999

Hewitt CO, Eszes CM, Sessions RB, Moreton KM, Dafforn TR, Takei J, Dempsey CE, Clarke AR, Holbrook JJ. A general method for relieving substrate inhibition in lactate dehydrogenases
Protein. Eng. 12 (6): 491-496 Jun 1999 [PDF]