Publication: In silico activation of KcsA K+ channel by lateral forces applied to the C-termini of inner helices

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Title In silico activation of KcsA K+ channel by lateral forces applied to the C-termini of inner helices
Authors/Editors* Denis B.Tikhonov and Boris S.Zhorov
Where published* Biophys. J.
How published* Journal
Year* 2004
Volume 87
Number 0
Pages 1526-1536
Publisher xxxxx
Crystallographic studies of K+ channels in the closed (KcsA) and open (MthK) states suggest that Gly99 (KcsA numbering) in the inner helices serves as a gating hinge during channel activation (Jiang et al. 2002. Nature, 417:515-526). However, some P-loop channels have larger residues in the corresponding position. The comparison of X-ray structures of KcsA and MthK shows that channel activation alters backbone torsions and helical H-bonds in residues 95-105. Importantly, the changes in Gly99 are not the largest ones. This raises questions about the mechanism of conformational changes upon channel gating. In this work, we have built a model of the open KcsA using MthK as a template and simulated opening and closing of KcsA by constraining C-ends of the inner helices at a gradually changing distance from the pore axis without restraining mobility of the helices along the axis. At each imposed distance, the energy was Monte Carlo-minimized. The channel-opening and channel-closing trajectories arrived to the structures in which the backbone geometry was close to that seen in MthK and KcsA, respectively. In the channel-opening trajectory, the constraints-induced lateral forces caused kinks at midpoints of the inner helices, between Val97 and Gly104 but did not destroy inter-domain contacts, the pore helices, and the selectivity filter. The simulated activation of the Gly99Ala mutant yielded essentially similar results. Analysis of inter-residue energies shows that the N-terminal parts of the inner helices form strong attractive contacts with the pore helices and the outer helices. The lateral forces induce kinks at the position where the helix-breaking torque is maximal and the intersegment contacts vanish. This mechanism may be conserved in different P-loop channels.
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