MD simulations of Cav and hERG
Please notice these positions are no longer vacant.

Drug dissociation pathways from resting state ion channels

It is commonly accepted that small molecules that block the passage of ions physically occlude the pore of ion channels. In order to gain access to the water filled cavity, the channel gates, formed by S6 helices have to open. However, recovery from block might not necessarily depend on channel opening, but various blockers might dissociate from closed channel states. The crystal structure complex of the potassium channel KcsA with a bound tetrabutylammonium (Faraldo-Gómez et al., 2007, Johannan et al., 2007) provides a good starting point to analyze drug dissociation pathways.
Workplan: The PhD student will use computational methods to derive hypotheses about mechanisms that lead to drug dissociation from potassium and calcium channels. Various dissociation scenarios, e.g. via the open and closed inner channel gates will be simulated using MD simulation protocols. Predictions made by the computational models will be tested experimentally with wild type and mutant channels.
Methods: The student will learn and apply the following techniques: molecular dynamics simulations of ion channel - drug complexes, force probe MD simulations, free energy calculations and homology modeling and model refinement of hERG and Cav1.2 channels.

Analysis of voltage dependence of ion channel blockers

Voltage-gated ion channels are membrane proteins that open and closed in response to voltage changes across the membrane. Physical occlusion of ion channel pores by charged molecules is often voltage dependent (e.g. devapamil block of Cav1.2 channels, Beyl et al., 2007). However, we have recently identified a calcium channel blocker, which is only weakly voltage dependent. Generally, the molecular mechanism underlying the voltage dependence of small molecules is poorly understood.  
Workplan: The PhD student will perform molecular dynamics simulations to derive hypotheses about mechanisms of voltage dependence of ion channel block. Guided by validated homology models of Cav1.2 and hERG (Stary et al. 2008, Stary et al. 2010) drug-receptor-interactions will be studied in detail. Docking studies and MD simulations will allow accurate analyses of the generated complexes. Membrane potential changes, included in MD simulations protocols will allow a detailed analysis of how drugs respond to different transmembrane potentials.
Methods: The student will learn and apply the following techniques: drug docking studies, molecular dynamics simulations, free energy calculations and homology modeling of voltage sensing domains of hERG and Cav1.2 channels.