Detailansicht

Molecular Modeling of Voltage-gated Calcium channels

Chonticha Suwattanasophon

Art der Arbeit

Dissertation

Universität

Universität Wien

Fakultät

Fakultät für Chemie

Betreuer*in

Peter Wolschann

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DOI

10.25365/thesis.21370

URN

urn:nbn:at:at-ubw:1-29535.71835.158469-6

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Abstracts

Abstract

(Englisch)

Ion channels are important molecular targets for the treatment of human diseases. They are responsible for the transport of ions (e.g. potassium and calcium) through cellular membranes. Calcium entry through voltage-gated calcium channels (CaV) initiates electrical impulses, sensory processes, muscle contraction, secretion of hormones and neurotransmitters, and other key cellular functions. Some specific organic compounds (drugs) can inhibit the ion flow, which consequently affects the cellular metabolism. Defective ion channels result in a variety of human diseases such as cardiovascular disease, night blindness and familial hemiplegic migraine, which are termed channelopathies. Theoretical methods are used to obtain the detailed information about the structure and function of ion channels and the association complexes of ligands with the channels. Homology modeling based on the related potassium and sodium channel structures is used to create models for the diverse states of the channels. Subsequent docking studies allow the investigation of the interaction of drugs with the internal pore of the channels. Molecular Dynamics simulations and Molecular Docking procedures are methods which give insight into the molecular basis of the biological activities. Development of the model and subsequent refinement based on the theoretical considerations and mutation data resulted not only in a better understanding of the action mechanisms of ion channels but furthermore increases our knowledge about the voltage dependent opening and closing mechanism and allow a more detailed investigation of drug interaction mechanisms. This thesis focuses on the mechanism and the structure of Cav1.2 calcium channel of closed and open pore region conformation. The Cav1.2 calcium channel belongs to the superfamily of voltage gated ion channels where crystal structures are not available. The closed model has been built based on the crystal structure of KcsA, MlotiK, Nak and a model of the bacterial sodium channel NaChBac. The structure of the open conformation was taken from Stary et al, 2009. At almost the end of the thesis in June 2011, a new voltage-gated sodium channel which shares the same highly conserved FxxxTxExW motif with calcium channel was published. Then, the newest homology model of Cav1.2 was built based on the new voltage-gated sodium channel crystal structure. Molecular docking of verapamil, its derivatives and qDiltiazem to the Cav1.2 open conformation using several Molecular Docking program packages (e.g. Glide and MOE) was performed to compare the best fitting results and to investigate the interaction of drugs with the internal pore of the channels. The results show that all drugs share similar results where the ligands are located in the same region between IIIS6 and IVS6 and the positively charged nitrogen atom of all ligands binds between the glutamic acids E1145 and E1446. The best fitting of verapamil, D619, T13 and qDiltiazem in Cav1.2 open conformation was used to perform MD simulations. A small variation in lipid composition can influence protein activity such as fluidity and lipid packing. Cholesterol is one of the main lipid components of the plasma membrane in mammalian cells, and is known to influence many ion channels. Here, we focus on how cholesterol interacts with Cav1.2 channels in open and closed conformation, applying molecular dynamicIon channels are important molecular targets for the treatment of human diseases. They are responsible for the transport of ions (e.g. potassium and calcium) through cellular membranes. Calcium entry through voltage-gated calcium channels (CaV) initiates electrical impulses, sensory processes, muscle contraction, secretion of hormones and neurotransmitters, and other key cellular functions. Some specific organic compounds (drugs) can inhibit the ion flow, which consequently affects the cellular metabolism. Defective ion channels result in a variety of human diseases such as cardiovascular disease, night blindness and familial hemiplegic migraine, which are termed channelopathies. Theoretical methods are used to obtain the detailed information about the structure and function of ion channels and the association complexes of ligands with the channels. Homology modeling based on the related potassium and sodium channel structures is used to create models for the diverse states of the channels. Subsequent docking studies allow the investigation of the interaction of drugs with the internal pore of the channels. Molecular Dynamics simulations and Molecular Docking procedures are methods which give insight into the molecular basis of the biological activities. Development of the model and subsequent refinement based on the theoretical considerations and mutation data resulted not only in a better understanding of the action mechanisms of ion channels but furthermore increases our knowledge about the voltage dependent opening and closing mechanism and allow a more detailed investigation of drug interaction mechanisms. This thesis focuses on the mechanism and the structure of Cav1.2 calcium channel of closed and open pore region conformation. The Cav1.2 calcium channel belongs to the superfamily of voltage gated ion channels where crystal structures are not available. The closed model has been built based on the crystal structure of KcsA, MlotiK, Nak and a model of the bacterial sodium channel NaChBac. The structure of the open conformation was taken from Stary et al, 2009. At almost the end of the thesis in June 2011, a new voltage-gated sodium channel which shares the same highly conserved FxxxTxExW motif with calcium channel was published. Then, the newest homology model of Cav1.2 was built based on the new voltage-gated sodium channel crystal structure. Molecular docking of verapamil, its derivatives and qDiltiazem to the Cav1.2 open conformation using several Molecular Docking program packages (e.g. Glide and MOE) was performed to compare the best fitting results and to investigate the interaction of drugs with the internal pore of the channels. The results show that all drugs share similar results where the ligands are located in the same region between IIIS6 and IVS6 and the positively charged nitrogen atom of all ligands binds between the glutamic acids E1145 and E1446. The best fitting of verapamil, D619, T13 and qDiltiazem in Cav1.2 open conformation was used to perform MD simulations. A small variation in lipid composition can influence protein activity such as fluidity and lipid packing. Cholesterol is one of the main lipid components of the plasma membrane in mammalian cells, and is known to influence many ion channels. Here, we focus on how cholesterol interacts with Cav1.2 channels in open and closed conformation, applying molecular dynamics simulations. We used different lipid compositions, pure POPC and mixture POPC/CHOL bilayers to obtain information and to provide a first hint about the possible effects by which cholesterol influences Cav1.2 channels. A mechanistic understanding of the molecular and structural details of ion channels in general and about the underlying principles of channelopathies raises hopes of improving and developing better targeted drugs in the future. s simulations. We used different lipid compositions, pure POPC and mixture POPC/CHOL bilayers to obtain information and to provide a first hint about the possible effects by which cholesterol influences Cav1.2 channels. A mechanistic understanding of the molecular and structural details of ion channels in general and about the underlying principles of channelopathies raises hopes of improving and developing better targeted drugs in the future.

Autor*innen

Chonticha Suwattanasophon

Haupttitel (Englisch)

Molecular Modeling of Voltage-gated Calcium channels

Paralleltitel (Englisch)

Molecular Modeling of Voltage-gated Calcium channels

Publikationsjahr

2012

Umfangsangabe

III, 175 S.

Sprache

Englisch

Beurteiler*innen

Gerhard Ecker ,

Dusanka Janezic

Klassifikation

33 Physik > 33.99 Physik: Sonstiges

AC Nummer

AC09422323

Utheses ID

19112

Studienkennzahl

UA | 091 | 411 | |

Detailansicht

Abstracts

Schlagwörter