Probing the energy landscape of activation gating of the bacterial potassium channel KcsA

The bacterial potassium channel KcsA, which has been crystallized in several conformations, offers an ideal model to investigate activation gating of ion channels. In this study, essential dynamics simulations are applied to obtain insights into the transition pathways and the energy profile of KcsA...

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Bibliographic Details
Published in:PLoS computational biology 2013-05, Vol.9 (5), p.e1003058
Main Authors: Linder, Tobias, de Groot, Bert L, Stary-Weinzinger, Anna
Format: Article
Language:English
Subjects:
Bacterial Proteins - chemistry
Bacterial Proteins - metabolism
Bioenergetics
Biological transport, Active
Biology
Chemistry
Crystal structure
Energy metabolism
Lipids
Molecular Dynamics Simulation
Physics
Physiological aspects
Potassium channels
Potassium Channels - chemistry
Potassium Channels - metabolism
Principal Component Analysis
Protein Conformation
Proteins
Standard deviation
Studies
Thermodynamics
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Summary:The bacterial potassium channel KcsA, which has been crystallized in several conformations, offers an ideal model to investigate activation gating of ion channels. In this study, essential dynamics simulations are applied to obtain insights into the transition pathways and the energy profile of KcsA pore gating. In agreement with previous hypotheses, our simulations reveal a two phasic activation gating process. In the first phase, local structural rearrangements in TM2 are observed leading to an intermediate channel conformation, followed by large structural rearrangements leading to full opening of KcsA. Conformational changes of a highly conserved phenylalanine, F114, at the bundle crossing region are crucial for the transition from a closed to an intermediate state. 3.9 µs umbrella sampling calculations reveal that there are two well-defined energy barriers dividing closed, intermediate, and open channel states. In agreement with mutational studies, the closed state was found to be energetically more favorable compared to the open state. Further, the simulations provide new insights into the dynamical coupling effects of F103 between the activation gate and the selectivity filter. Investigations on individual subunits support cooperativity of subunits during activation gating.
ISSN:1553-7358
1553-734X
1553-7358
DOI:10.1371/journal.pcbi.1003058