Ion Conductance Through Potassium Channels

Köpfer, David Alexander

Studied by Molecular Dynamics Simulations

dc.contributor.advisor	Groot, Bert De Prof. Dr.
dc.contributor.author	Köpfer, David Alexander
dc.date.accessioned	2015-10-01T08:24:04Z
dc.date.available	2015-10-01T08:24:04Z
dc.date.issued	2015-10-01
dc.identifier.uri	http://hdl.handle.net/11858/00-1735-0000-0023-9634-D
dc.identifier.uri	http://dx.doi.org/10.53846/goediss-5292
dc.language.iso	eng	de
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc	530	de
dc.title	Ion Conductance Through Potassium Channels	de
dc.title.alternative	Studied by Molecular Dynamics Simulations	de
dc.type	doctoralThesis	de
dc.contributor.referee	Groot, Bert De Prof. Dr.
dc.date.examination	2015-04-20
dc.subject.gok	Physik (PPN621336750)	de
dc.description.abstracteng	K + channels are at the basis of fundamental physiological processes in virtually all cells. These functions range from maintaining cell homeostasis to being involved in the nerve signaling process. Their basic function lies in their ability to efficiently mediate the passage of K + ions across the membrane along their chemical gradient at rates close to the diffusion limit, while at the same time denying the passage of other physiologically relevant ions—foremost the smaller Na + ions. K + channels form the largest and most diverse group of ion channels, whose duration and magnitude of electric response differs in response to a variety of external stimuli among their members. For K + channels, a wealth of data is available from over half a century of electrophysiology and more recently from an increasing number of atomistic structures, solved by x-ray crystallography. Based on this data, the selectivity filter (SF), the narrowest passage for ions at the extracellular mouth of the channel, has been identified as a core functional element of all K + channels. The SF has shown to instantiate the K + selectivity of K + ions over other ion species, while allowing almost barrierless transition of K + ions. Furthermore, the SF has shown to act as a gate regulating the current through the channel. In this thesis, we employ MD simulations to combine structural information from x-ray crystallography with functional data from electrophysiology to gain insights into the mechanics of the SF of K + channel in general. For direct com- parison to the electrophysiological single channel recordings we employ the com- putational electrophysiology method, a setup which allows to subject the channel to a sustained trans-membrane voltage by maintaining an ionic imbalance. Using this setup we were able to induce spontaneous ion permeation across the chan- nel, allowing direct measurement of the channel’s most important observable—its current. Based on this setup, we looked at the permeation process itself and found that— contrary to the textbooks—K + ions pass through the SF with direct ionic contacts, rather than with interspersed water molecules. Indeed, we found evidence that these direct contacts are key for efficient ion translocation in many different K + channels. Additionally we investigated the role of the SF in the permeation process and found a concerted motion of the SF backbone carbonyl-oxygen atoms during6 the ion permeation process, that serve to shield the high charge density of the ions. By restraining the SF flexibility we found this motion to be extremely sensitive, to even sub-Ångström perturbations. These findings should help our understanding of the impact on channel conductance from small mutations in the vicinity of the SF. Furthermore, we found the same setup under biionic conditions capable of reproducing the channel selectivity for K + ions over Na + ions. The data from these simulations presents a solid basis to test various kinetic and thermodynamic models of ion permeation, that have been proposed. Apart from the permeation of ions, we also looked at changes of the SF structure and their impact on the channel conductance. Using the rapidly inactivating K + channel hERG, we showed how alterations in the supporting hydrogen bond net- work behind the SF are capable of switching the SF conformation between a high K + concentration state and a low K + concentration state, which helps to under- stand how the conductance changes in C-type inactivation might be regulated. To gain further insights into this inactivation process we compared long simulations of wild type (WT) and inactivation-impaired mutants of K + channels. The differ- ence between these two channels shows a structural rearrangement that impacts on the SF and the gating helices at the same time and seems to be mediated via the pore helices (PH). Such a mechanism could explain the experimentally observed coupling between gating and C-type inactivation. These deep insights into the channel mechanics can provide a basis for better models of drugs designed to target K + channels and may also prove useful in understanding hereditary diseases that are grounded in channel mutations.	de
dc.contributor.coReferee	Ficner, Ralf Prof. Dr.
dc.subject.eng	Molecular Dynamics	de
dc.subject.eng	Ion Channels	de
dc.subject.eng	Potassium Channels	de
dc.subject.eng	KcsA	de
dc.subject.eng	computational elecrophysiology	de
dc.identifier.urn	urn:nbn:de:gbv:7-11858/00-1735-0000-0023-9634-D-1
dc.affiliation.institute	Fakultät für Physik	de
dc.identifier.ppn	836010299

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Das Dokument erscheint in:

GGNB - Göttinger Graduiertenzentrum für Neurowissenschaften, Biophysik und molekulare Biowissenschaften [1114]
GGNB - Göttingen Graduate Center for Neurosciences, Biophysics and Molecular Biosciences

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