Homology Models and Molecular Dynamics Simulations of the Tetramerization Domain of Voltage-Gated Potassium Channels Kv1.1-Kv1.6

• Main Authors: Chin-Wen Chen, 陳錦文
• Other Authors: Hsuan-Liang Liu
• Format: Others
• Language: en_US
• Published: 2005
• Online Access: http://ndltd.ncl.edu.tw/handle/vcrg8r

碩士 === 國立臺北科技大學 === 生物科技研究所 === 93 === The homology models of the tetramerization (T1) domain of six eukaryotic potassium channels, Kv1.1-Kv1.6, were constructed based on the crystal structure of the Shaker T1 domain. The results of amino acid sequence alignment indicate that the T1 domains of these K+ channels are highly conserved, with the similarities varying from 77 % between Shaker and Kv1.6 to 93 % between Kv1.2 and Kv1.3. The homology models reveal that the T1 domains of these Kv channels exhibit similar folds as those of Shaker K+ channel. These models also show that each T1 monomer consists of three distinct layers, with N-terminal layer 1 and C-terminal layer 3 facing the cytoplasm and the membrane, respectively. Layer 2 exhibits the highest structural conservation because it is located around the central hydrophobic core. For each Kv channel, four identical subunits assemble into the homotetramer architecture around a four-fold axis through the hydrogen bonds and salt bridges formed by 15 highly conserved polar residues. The narrowest opening of the pore is formed by the four conserved residues corresponding to R115 of the Shaker T1 domain. The homology models of these Kv T1 domains provide particularly attractive targets for further structure-based studies. Several molecular dynamics simulations towards the Shaker and Kv1.1 T1 domains were conducted at various temperatures. Our results show that the Shaker T1 domain exhibit higher structural integrity than the Kv1.1 T1 domain at all temperatures examined. In addition, the thermal unfolding of the Shaker T1 domain begins at layer 3. In contrast, layers 1and 2 exhibit higher structural stability because layer 1 remains more hydrogen bonding interactions at elevated temperatures and layer 2 is located in the highly conserved hydrophobic core. Ile121 in the Shaker T1 domain plays an important role in disrupting the loop between helices 4 and 5. During the thermal unfolding process, the newly formed hydrophobic interactions between Ala120, Ile121, Leu122, Leu131, and Leu151 may distort the native contact between layers 2 and 3 of the T1 domain.