Laboratory of Molecular Biophysics
Laboratory Journal 2001
Prof. M. S. P. Sansom

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Mark Sansom

Computational Studies of Membrane Proteins: Sequences, Structures and Simulations

Mark S.P. Sansom, Indira Shrivastava, Phil Biggin, Hyunji Kim, Joanne Bright, Carmen Domene, Marc Baaden, John Tate, Martin Ulmschneider, Richard Law, Charlotte Capener, José Faraldo-Gómez, George Patargias, Oliver Beckstein, Yalini Pathy, Pete Bond, Jonathan Cuthbertson, Frank Cordes, Sundeep Deol, Jeff Campbell, Christoph Meier.

Research in this group involves the use of structural bioinformatics and molecular simulation methods to study ion channels and related membrane transport proteins. The overall aim of our work is to understand the relationship between (dynamic) structure and physiological function of ion channels and other membrane proteins.

Integral membrane proteins account for ca. 30% of all genes, and include ca. 50% of major target systems for development of new drugs. They are responsible for a diversity of functions, including signalling and transport across membranes. Recent advances in membrane protein crystallography have significantly enhanced our knowledge of membrane protein structures. However, to understand the relationship between structures and biological functions, it is necessary to characterise the dynamics of membrane proteins in the complex, anisotropic environment provided by a lipid bilayer. We are using computational approaches to explore the conformational dynamics of membrane proteins, to relate their dynamic properties to their biological functions, and to refine methods of structure prediction for application to those membrane proteins (the vast majority) for which experimental structural data remain unavailable.

Ion channels mediate electrical excitability in neurons and muscle. Three-dimensional structures for channels may be combined with computer simulations to permit rigorous exploration of structure-function relations of channels. By combining atomistic simulations (in which all atoms of the channel molecule, water and ions are treated explicitly) with continuum methods (in which the description of the channel system is considerably simplified) it is possible to simulate some of the physiological properties of channels. An overview of this work is provided in [1].

Figure 1. K channel in a lipid bilayer.

In addition to simulation studies of a number of ion channels, we are also interested in applying these, and related, computational approaches to other membrane proteins, including a number of transporters, both bacterial and mammalian. Methods being employed include: structural bioinformatics; molecular modelling on the basis of sparse structural data; and simulations based on experimental structures and homology models.

Our research activities can be classified into the following areas:

Ion channel simulation and theoretical studies.

Basic theoretical approaches on simplified systems - ion permeation and selectivity; gating [2, 3, 4].
Figure 2. Model of a Hydrophobic Nanopore.
Viral [5] and peptide [6] channels as test systems for developing new simulation approaches.
Potassium channels - computational chemistry and MD simulation studies of permeation [7, 8, 9, 10], block and gating [11] of KcsA [12]; homology modelling of Kv [13], Kir [14, 15] and TWIK channels.
Ligand-gated ion channels - nAChR (electrostatics, M2 helix and gating) [16]; GluR (modelling; simulations of extracellular domain with respect to gating) [17].
Development of methodologies for long timescale events (permeation; gating) [18, 19, 20].

Transport proteins - bacterial and mammalian.

Bacterial outer membrane proteins - OmpA (a putative channel) [21]; FhuA (a Fe³⁺ transporter that undergoes a conformational change during active transport) [22, 23]; OMPLA (a bacterial outer membrane lipase).
GlpF and Aqp1 (two members of the aquaporin family of transporters) - simulation studies of the molecular basis of rapid passive transport and selectivity (for glycerol vs. water) [4, 24].
Figure 3. Bacterial membrane proteins - OmpA (left) and GlpF (right).

Bioinformatics of membrane proteins.

Comparative genomics of ion channels and channel-associated membrane proteins to identify possible 'networks of interactions'
Structural bioinformatics of membrane proteins - using data-mining approaches to uncover principles of membrane protein structure and stability [25].

Membrane protein structure modelling from sparse experimental data.

Simulation approaches to membrane protein stability - towards general rules of e.g. TM helix/bilayer interactions.
Development of empirical potentials from data-mining (see above) to aid modelling.
Restraints-based modelling, exploiting incomplete or low resolution structural data e.g. mutagenesis, spectroscopy, electron microscopy.

Membrane active antimicrobial peptides.

Mode of interaction of anti-microbial peptides with lipid bilayers - simulations; selectivity [26, 27].
Simulation studies of non-bilayer perturbations ('toroidal pores') induced by peptides.

In addition to these specific areas of investigation, we have also been active in developing high performance computing and E-science facilities within the university. HPC is essential to provide the infrastructure for cutting edge simulations of large systems. E-science, and in particular GRID computing, will play an increasingly important role, especially in the context of a new project to develop a prototype biomolecular simulation database for the UK (a joint BBSRC funded project with colleagues from the Universities of Southampton, Birmingham, Nottingham, York and at Birkbeck College, London).

Figure 4. A Biomolecular simulation GRID for the UK.

References