Molecular dynamics and continuum electrostatics studies of inactivation in the HERG potassium channel.
Fast inactivation of the HERG potassium channel plays a critical role in normal cardiac function. Malfunction of these channels due to either genetic mutations or blockade by drugs leads to cardiac arrhythmias. An unusually long S5-P linker in the outer mouth of HERG is implicated in the fast inactivation mechanism. To examine the role of the S5-P linker in this inactivation mechanism, we study the permeation properties of the open and inactive states of a recent homology model of HERG. This model was constructed using the KcsA potassium channel as a template and contains specific conformations of the S5-P linker in the open and inactive states. We perform molecular dynamics simulations on the HERG model, followed by free energy, structural, and continuum electrostatics calculations. Our free energy calculations lead to selectivity results of the model channel (K+ over Na+) that are different in some respects from those of other potassium channels but consistent with experimental observations. Our structural results show that, in the inactive state, the S5-P linkers move closer to the channel axis, possibly causing a steric hindrance to permeating K+ ions. Our electrostatics calculations reveal, in the inactive state, an electrostatic potential energy barrier of approximately 14 kT at the extracellular pore entrance, again sufficient to stop K+ ion permeation through the pore. These results suggest that a steric and/or electrostatic plug mechanism contributes to inactivation in the HERG homology model.
Kutteh
Ramzi
R
School of Physics, University of Sydney, Sydney, New South Wales 2006, Australia. r.kutteh@mailaps.org
Vandenberg
Jamie I
JI
Kuyucak
Serdar
S
D000595:Amino Acid Sequence; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D055672:Static Electricity; D013816:Thermodynamics; D013997:Time Factors
D051638:Ether-A-Go-Go Potassium Channels