Projects per year
Membrane ion channel, transport, and receptor proteins embedded within cell membranes carry out much of the membrane transport and communication functions of the cell. A class of ion channel proteins that respond to changes in membrane potential allow selective flow of ions across the cell membrane to generate action potentials in excitable tissue such as neurons or heart muscle. In collaboration with Jules Hancox in the School of Physiology and Pharmacology at Bristol, we are building atomic scale models of K+ channel proteins to understand the structural basis for the effects of channel mutations and for promiscuous drug binding in a heart K+ channel (hERG). hERG is important for maintaining normal electrical activity in the human heart.
Current work is focused on:
- simulating the binding of hERG channel blocking drugs to a range of hERG homology models to establish which structures provide the best models for matching with experimental drug block data (Figure 1).
Figure 1: Homology model of the hERG pore domain highlighting amino acids that are implicated in interaction with drugs that block hERG channels. [see Dempsey et al. (2014) J. Chem. Inf. Model. 2014, 54 (2), pp 601–612]
- constructing models of the full membrane domain of hERG and using molecular dynamics simulations in hydrated membranes (i) to understand the functional effects of channel mutations and (ii) to explore interactions between voltage sensor and pore domains that modulate channel gating in response to changes in membrane potential (Figure 2).
Figure 2: Homology model of the full hERG membrane domain tetramer (pore domain plus voltage sensor domains) constructed by Charlie Colenso. [see Colenso et al. (2013) J. Chem. Inf. Model. 2013, 53 (6), pp 1358–1370]
- addressing fundamental aspects of voltage-sensitive ion channel function using a combination of molecular dynamics simulation and functional studies (Figure 3).
Transfer of an arginine side chain (R534) through a hydrophobic "plug" or "seal" in two voltage sensor subunits (boxed in Figure 3) during molecular dynamics simulation of the membrane-embedded hERG model, mimics the gating charge transfer that underpins voltage sensor responses to changes in membrane voltage. The unique hydration properties of the arginine side chain determined by Phil Mason and George Neilson* in the Bristol Physics Department, likely underlies the role of arginine (over lysine) as a mobile charge carrier in voltage sensor domains (Figure 3 bottom). [*Mason et al. (2003) Proc. Natl. Acad. Sci. USA 100, 4557-4561]
Figure 3: ABOVE Movement of R534 side chain across the hydrophobic seal of a voltage sensor domain (boxed region) of the hERG model. BELOW During transfer the Arg side chain remains hydrated (green dotted lines indicate Arg-water or Arg-Asp hydrogen bonds). The hydrating O atoms lie in the plane of the side chain guanidine group. Note that for a lysine side chain a spherical distribution of hydrating O atoms is observed (bottom right). [see Colenso et al. (2014) Biophys. J. 2014, 107 (10), L25-L28]
Butler, A., Helliwell, M. V., Zhang, Y., Hancox, J. C. & Dempsey, C. E., 24 Jan 2020, In: Frontiers in Pharmacology. 10, 13 p., 1572.
Research output: Contribution to journal › Article (Academic Journal) › peer-reviewOpen AccessFile58 Downloads (Pure)
Electrophysiological characterization of the modified hERGT potassium channel used to obtain the first cryo‐EM hERG structureZhang, Y., Dempsey, C. E. & Hancox, J. C., 22 Oct 2020, (E-pub ahead of print) In: Physiological Reports. 8, 20, 13 p., e14568.
Research output: Contribution to journal › Article (Academic Journal) › peer-reviewOpen AccessFile14 Downloads (Pure)
Serine mutation of a conserved threonine in the hERG K+ channel S6-pore region leads to loss-of-function through trafﬁcking impairmentAl-Moubarak, E., Zhang, Y., Dempsey, C. E., Zhang, H., Harmer, S. C. & Hancox, J. C., 11 Jun 2020, In: Biochemical and Biophysical Research Communications. 526, 4, p. 1085-1091 7 p.
Research output: Contribution to journal › Article (Academic Journal) › peer-reviewOpen AccessFile35 Downloads (Pure)