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

Obiettivo

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.

Invito a presentare proposte

FP7-PEOPLE-2012-IOF
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Coordinatore

ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Contributo UE
€ 264 112,50
Indirizzo
BATIMENT CE 3316 STATION 1
1015 Lausanne
Svizzera

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Regione
Schweiz/Suisse/Svizzera Région lémanique Vaud
Tipo di attività
Higher or Secondary Education Establishments
Contatto amministrativo
Ursula Rothlisberger (Prof.)
Collegamenti
Costo totale
Nessun dato