| EPSRC Reference: |
EP/E014585/1 |
| Title: |
OPENING ION CHANNELS WITH A TRANS-CIS PROLINE SWITCH: A COMPUTATIONAL METADYNAMICS STUDY |
| Principal Investigator: |
Molteni, Professor C |
| Other Investigators: |
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| Project Partners: |
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| Department: |
Physics |
| Organisation: |
Kings College London |
| Scheme: |
Standard Research |
| Starts: |
01 January 2007 |
Ends: |
30 September 2008 |
Value (£): |
147,385
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| EPSRC Research Topic Classifications: |
| Biological membranes |
Biophysics |
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| EPSRC Industrial Sector Classifications: |
| No relevance to Underpinning Sectors |
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| Panel History: |
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Summary on Grant Application Form |
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Ligand-Gated ion Channels (LGICs) are important mediators in neuronal transmission and are involved in many neurological disorders, such as Alzheimer's and Parkinson's diseases. These receptors, located in the membrane of nerve cells, are large proteins, consisting of different subunits arranged around an ion-conducting central pore; each subunit is composed by an extracellular domain, a transmembrane domain and an intracellular domain. The activation of LGICs is initiated by the binding of a small neurotransmitter to the extracellular domain: this triggers a series of chemical events and conformational changes in the protein culminating with the opening (gating) of the channel: ions can then flood across the cell membrane modifying the cell activity. The most intriguing question concerning LGICs is how the binding of a small neurotransmitter in the extracellular domain translates into the opening of the channel in the transmembrane domain more than 50 + away. Recent experiments on the 5-hydroxytryptamine type 3 receptor (5-HT3R) led to the proposal that a specific proline amino-acid (Pro 8*), located at the apex of a loop between two transmembrane helices (M2-M3 loop), can act as a switch for ion channel gating by means of a trans-cis isomerisation and of its structural effects on the protein backbone. Since structural information on LGICs is limited, atomistic simulations can play a crucial role in verifying the gating mechanism supported by the experiments, providing additional insights. In particular, the goal of this exploratory computational project is to demonstrate whether the use of metadynamics (a novel simulation technique to explore the free energy surfaces of complex polyatomic systems) can provide an atomistic picture of the proposed gating mechanism. Using a combination of classical and quantum mechanical methods, we will start investigating the proline switch in a 20 amino-acid model peptide mimicking the 5-HT3R relevant (M2-M3) loop. We will assess the effects of proline mutations with proline analogues, preferring either the cis or the trans conformations, which in experiments produced functional or non-functional receptors, and evaluate the influence of the environment on the isomerisation mechanism. We will then increase the complexity of the model system, e.g. including the channel lining (M2) helix which is thought to be repositioned by the proline switch. Finally, we will extend the analysis to receptors of the same superfamily as 5-HT3R, searching for similar or alternative switches. The proposed research will lead to the development of protocols for the use of the metadynamics technique to study switching mechanisms in biomolecules.
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Key Findings |
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Potential use in non-academic contexts |
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This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
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Impacts |
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| Description |
This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk |
| Summary |
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| Date Materialised |
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Sectors submitted by the Researcher |
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This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
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