bi5009408_si_001.pdf (1 MB)
Mechanisms and Energetics of Potassium Channel Block by Local Anesthetics and Antifungal Agents
journal contribution
posted on 2014-11-04, 00:00 authored by Rong Chen, Ganna Gryn’ova, Yingliang Wu, Michelle L. Coote, Shin-Ho ChungMany
drug molecules inhibit the conduction of several families
of cation channels by binding to a small cavity just below the selectivity
filter of the channel protein. The exact mechanisms governing drug–channel
binding and the subsequent inhibition of conduction are not well understood.
Here the inhibition of two K+ channel isoforms, Kv1.2 and
KCa3.1, by two drug molecules, lidocaine and TRAM-34, is
examined in atomic detail using molecular dynamics simulations. A
conserved valine-alanine-valine motif in the inner cavity is found
to be crucial for drug binding in both channels, consistent with previous
studies of similar systems. Potential of mean force calculations show
that lidocaine in its charged form creates an energy barrier of ∼6 kT for a permeating K+ ion when the ion is crossing
over the drug, while the neutral form of lidocaine has no significant
effect on the energetics of ion permeation. On the other hand, TRAM-34
in the neutral form is able to create a large energy barrier of ∼10 kT by causing the permeating ion to dehydrate. Our results
suggest that TRAM-34 analogues that remain neutral and permeable to
membranes under acidic conditions common to inflammation may act as
possible drug scaffolds for combating local anesthetic failure in
inflammation.