VOLTSENS

Probing the sequence determinants of ion channel voltage sensing via computation: towards the design of custom-tailored voltage-sensing modules

Coordinatore	ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE    more  Organization address address: BATIMENT CE 3316 STATION 1 city: LAUSANNE postcode: 1015 contact info Titolo: Prof. Nome: Ursula Cognome: Rothlisberger Email: send email Telefono: +41 21 693 03 21 Fax: +41 21 693 03 20
Nazionalità Coordinatore	Switzerland [CH]
Totale costo	264˙112 €
EC contributo	264˙112 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2012-IOF
Funding Scheme	MC-IOF
Anno di inizio	2013
Periodo (anno-mese-giorno)	2013-05-01   -   2016-04-30

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE  Organization address address: BATIMENT CE 3316 STATION 1 city: LAUSANNE postcode: 1015 contact info Titolo: Prof. Nome: Ursula Cognome: Rothlisberger Email: send email Telefono: +41 21 693 03 21 Fax: +41 21 693 03 20	CH (LAUSANNE)	coordinator	264˙112.50

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 Obiettivo del progetto (Objective)

'Voltage sensing is a crucial property for a variety of proteins involved in many physiological functions (selective ion transport through membranes, enzymatic catalysis…). All these proteins achieve voltage sensing through the action of a 4 alpha-helix bundle module called the voltage-sensor domain (VSD). This transmembrane module achieves its function thanks to specific features, such as the presence of a large number of conserved charged or hydrophobic residues isolating the intracellular domain from the extracellular one. Despite these common features, nature achieves a surprising variability in terms of voltage-sensing properties, i.e., the thermodynamic and kinetic properties characterizing VSD activation span a wide range of values among the VSD superfamily. What are the residues responsible for such modulation and how this variability is achieved is not yet understood and is of great interest from a medical perspective, as it would shed light onto the effect of disease-involved mutation of crucial residues (channelopathies). This proposal offers to use the arsenal of computational methods derived from theoretical chemistry (molecular dynamics simulations using atomistic and polarizable force fields, free energy calculations, QM/MM calculations, force matching algorithms…) and bioinformatics (homology modeling, evolutionary modeling…) to unravel this question. The proposal unfolds in three steps: the first involves developing a robust framework to evaluate the thermodynamic and kinetic properties of activation of a specific VSD. The second consists in evaluating the impact of the mutation of specific residues on the parameters determined in step 1, while validating and refining the theoretical framework through comparison of these results to experimental ones from our collaborators. The final step consists in integrating this data in an evolutionary model including a variety of VSDs.'