Laboratory of Molecular Biophysics
Laboratory Journal 2003
Mark S. P. Sansom

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Mark S. P. Sansom

Biomolecular simulations and structural bioinformatics of membrane proteins

Membrane proteins: biological importance

The overall theme of work in my group is to employ a range of computational techniques (structural bioinformatics, molecular modelling, MD simulations, etc.) to membrane proteins. Membrane proteins play keys role in cell biology e.g. as ion channels, drug receptors, and solute transporters. Indeed, it has been estimated that ~25% of genes code for membrane proteins, and that ca. 50% of potential new drug targets are membrane proteins. In particular we are interested in ion channels, membrane transport proteins, and bacterial outer membrane proteins.

Structural bioinformatics and Simulations

Despite the central importance of membrane proteins, the number of high resolution structures (from X-ray diffraction and more recently from NMR) remains small, amounting to only ca. 45 membrane proteins. Furthermore, those membrane proteins for which structures have been determined are mainly bacterial. Very few structures have been determined for mammalian (let alone human) membrane proteins. Of course, given sufficient time and the ongoing advances in experimental techniques, the number of structures will rise. However, given the paucity of structural information we wish to use computational methods to extrapolate from the available experimental data. There are two ways in which computational methods are valuable. Firstly, they can be used (via molecular dynamics simulations) to probe the relationship between static/average structures and the resultant dynamics of the protein, which in turn plays an important part in membrane protein function. The second approach is to analyze known membrane protein structures in order to reveal underlying principle of membrane protein structure and stability, thus (ultimately) aiding structure prediction.

Current group members and their research.

(for further details please see http://sansom.biop.ox.ac.uk)

Shiva Amiri

bioinformatics and molecular modeling studies of the nicotinic acetylcholine receptor (nAChR) and related ion channels

Yalini Arinaminpathy

structural bioinformatics analysis of membrane proteins
simulation studies of ligand-induced conformational changes in glutamate receptors: GluR0 and GluR2

Oliver Beckstein

principles of hydrophobic gating in ion channels and model nanopores
MD simulations and hydrophobic gating of nAChR
(see Figure 1 at end of section)

Dr Daniele Bemporad

modelling and simulation studies of the interactions between ion channels and peptide toxins
development of methods for simulation of channel-toxin complexes

Dr Phil Biggin

simulation of long timescale events underlying channel and receptor gating
modeling and database studies of ligand-gated ion channels

Pete Bond

molecular dynamics simulations conformational changes underlying pore formation by bacterial outer membrane proteins: OmpA and OpcA
simulation of outer membrane protein dynamics vs. environment (crystal vs. micelle vs. bilayer) in relation to experimental data
(see Figure 2 at end of section)

Jeff Campbell

modeling and simulation studies of ABC transporters: HisP and P-glycoprotein
combined experimental and computational studies of SUR1 (with Prof. F. Ashcroft)

Katherine Cox

MD simulations of outer membrane proteins: OmpX and PagP
comparison of simulation behaviour of X-ray and NMR structures of outer membrane proteins

Jonathan Cuthbertson (joint supervision with Dr Declan Doyle)

analysis and application of transmembrane helix prediction methods
genome wide analysis and comparison of membrane protein topologies

Sundeep Deol

protein-lipid interactions: structural bioinformatics and molecular dynamics studies
simulation studies of lipid/protein interactions in KcsA (with Dr. C. Domene) and MAO
(see Figure 3 at end of section)

Robert d'Rozario

conformational dynamics of proline-induced hinges in transmembrane _-helices
proline-induced helices and bacterial transport proteins

Dr Alessandro Grottesi

simulation of interaction of voltage-gated K-channel interactions with peptide toxins
simulation studies of K channels, including KirBac (with Dr. C. Domene)

Dr Shozeb Haider

modeling and simulation studies of inward rectifier K (Kir) channels
simulation of Kir channel intracellular domains

Sylvanna Ho

simulation studies of membrane proteins for biosensors (with Dr. H. Hartigan, NPL)

John Holyoake

conformation dynamics of lactose permease

Dr Andrew Hung

computational studies of protein nanomechanical properties
simulation studies of nAChR dynamics

Anthony Ivetac

database and simulation approaches to ABC transporters

Jennifer Johnston

simulation and structural bioinformatics studies of TM helices with 'proline-free' distortions
simulation studies of model channels formed by M2-derived peptides

Samantha Kaye

database and simulation approaches to glutamate receptors

Syma Khalid

high throughput simulations of outer membrane proteins
towards an outer membrane protein simulation database

George Patargias

simulation studies of permeation and selectivity in GlpF
computational studies of GlpF/glycerol kinase interactions

Dr Jorge Pikunic

very large scale simulations of bacterial outer membranes using HPCx
MD simulations of bacterial outer membrane protein BtuB

Zara Sands

simulation studies of K channel gating

Dr Kaihsu Tai

BioSimGrid: A Grid database for biomolecular simulations
nAChR molecular mechanics

Loredana Vaccaro

simulation studies of F-ATPase c-subunit: stability vs. environment
modeling and simulations studies of the AcrB/TolC system

Dr Bing Wu

E-science for BioSimGrid (with Prof. P. Jeffreys)

Figures:

	Figure 1: Simulation studies of ions in the nAChR pore domain
	Figure 2: OpcA in a model (DMPC) membrane
	Figure 3: Model of a MAO dimer attached to a lipid bilayer

Some Recent Publications.

Campbell, J.D. Sansom, M.S.P. and Ashcroft, F.M. (2003) Structural insights into the function of the human sulphonylurea receptor: a potassium channel regulator EMBO Reports 4:1038-1042
Domene, C., Bond, P.J., Deol, S.S. and Sansom, M.S.P. (2003) Lipid-protein interactions and the membrane/water interfacial region. J. Amer. Chem. Soc. 125:14966-14967.
Stenham, D.R., Campbell, J.D., Sansom, M.S.P., Higgins, C.F., Kerr, I.D. and Linton, K.J. (2003) An atomic detail model for the human ATP binding cassette transporter P-glycoprotein derived from disulphide cross-linking and homology modeling. FASEB J. 17:2287-2289.
Domene, C., Bond, P. and Sansom, M.S.P. (2003) Membrane protein simulation: ion channels and bacterial outer membrane proteins. Adv. Prot. Chem. 66:159-193
Beckstein, O., Biggin, P.C., Bond, P.J., Bright, J.N., Domene, C., Grottesi, A., Holyoake, J. and Sansom, M.S.P. (2003) Ion channel gating: insights via molecular simulations FEBS Lett. 555:85-90.
Domene, C., and Sansom, M.S.P. (2003) A potassium channel, ions and water: simulation studies based on the high resolution X-ray structure of KcsA. Biophys. J. 85:2787-2800.
Arinaminpathy, Y., Biggin, P.C., Shrivastava, I.H. and Sansom, M.S.P. (2003) A prokaryotic glutamate receptor: homology modelling and molecular dynamics simulations of GluR0. FEBS Lett. 553:321-327
Domene, C., Haider, S. and Sansom, M.S.P. (2003) Ion channel structures: a review of recent progress. Curr. Opin. Drug Discov. Develop. 6:611-619
Pang, A., Arinaminpathy, Y., Sansom, M.S.P. and Biggin, P.C. (2003) Interdomain dynamics and ligand Binding: molecular dynamics simulations of glutamine binding protein. FEBS Lett. 550:168-174.
Wu, B., Tai, K., Murdock, S., Ng, M.G., Johnston, S., Fangohr, H., Jeffreys, P., Cox, J., Essex, J., Sansom, M.S.P. (2003) BioSimGRID: a distributed database for biomolecular simulations. Proc. UK e-Science All Hands Meeting 2003 (ISBN 1-904425-11-9) pp. 412-419
Baaden, M., Meier, C. and Sansom, M.S.P. (2003) A molecular dynamics investigation of mono- and dimeric states of the outer membrane enzyme OMPLA J. Mol. Biol. 331:177-189
Bond, P. and Sansom, M.S.P. (2003) Membrane protein dynamics vs. environment: simulations of OmpA in a micelle and in a bilayer J. Mol. Biol. 329:1035-1053
Trapp, S., Haider, S., Jones, P., Sansom, M.S.P. and Ashcroft, F.M. (2003) Identification of residues contributing to the ATP-binding site of Kir6.2 EMBO J. 22:2903-2912
Beckstein, O. and Sansom, M.S.P. (2003) Liquid-vapor oscillations of water in hydrophobic nanopores. Proc. Natl. Acad. Sci. USA 100:7063-7068
Campbell, J.D, Biggin, P.C., Baaden, M. and and Sansom, M.S.P. (2003) Extending the structure of an ABC transporter to atomic resolution: modelling and simulation studies of MsbA Biochem. 42:3666-3673
Biggin, P.C. and Sansom, M.S.P. (2003) Mechanosensitive channels: stress relief. Curr. Biol. 13:R183-R185.
Grottesi, A. and Sansom, M.S.P. (2003) Molecular dynamics simulations of a K+-channel blocker: Tc1 Toxin from Tityus cambridgei. FEBS Lett. 535:29-33
Bright, J.N. and Sansom, M.S.P. (2003) The flexing/twirling helix: exploring the flexibility about molecular hinges formed by proline and glycine motifs in transmembrane helices. J. Phys. Chem. B 107:627-636