Data di Pubblicazione:
2007
Citazione:
Molecular dynamics simulation of the cytosolic mouth in Kcv-type potassium channels / S. Tayefeh, T. Kloss, G. Thiel, B. Hertel, A. Moroni, S.M. Kast. - In: BIOCHEMISTRY. - ISSN 0006-2960. - 46:16(2007 Apr 24), pp. 4826-4839. [10.1021/bi602468r]
Abstract:
The functional effect of mutations near the intracellular mouth of the short viral Kcv potassium channel was studied by molecular dynamics simulations. As a model system we used the analogously mutated and truncated KirBac1.1, a channel with known crystal structure that shares genuine local sequence motifs with Kcv. By a novel simulated annealing methodology for structural averaging, information about the structure and dynamics of the intracellular mouth was extracted and complemented by Poisson-Boltzmann and 3D-RISM (reference interaction site model) integral equation theory for the determination of the K+ free energy surface. Besides the wild-type analogue of Kcv with its experimental reference activity (truncated KirBac1.1), two variants were studied: a deletion mutant where the N-terminus is further truncated by eight amino acids, showing inactivity in the Kcv reference system, and a point mutant where the kink-forming proline at position 13 is substituted by alanine, resulting in hyperactivity. The computations reveal that the change of activity is closely related to a hydrophilic intracellular constriction formed by the C-terminal residues of the monomers. Hyperactivity of the point mutant is correlated with both sterical and electrostatic factors, while inactivity of the deletion mutant is related to a loss of specific salt bridge patterns between the C- and N-terminus at the constriction and to the consequences for ion passage barriers, as revealed by integral equation theory. The cytosolic gate, however, is probably formed by the N-terminal segment up to the proline kink and not by the constriction. The results are compared with design principles found for other channels.
Tipologia IRIS:
01 - Articolo su periodico
Elenco autori:
S. Tayefeh, T. Kloss, G. Thiel, B. Hertel, A. Moroni, S.M. Kast
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