A Comprehensive Dynamical Model for Human CaV1.2 Ion Channel: Structural and Functional Studies

• Author / Creator

  Tianhua Feng

• Human CaV1.2 is a voltage-gated calcium channel (VGCC), which plays an essential role to maintain a normal cardiac function. Any abnormalities in CaV1.2 can lead to serious cardiac diseases (e.g. cardiac arrhythmias and Timothy syndrome). Thus, understanding the structure-function-dynamics relationships of CaV1.2 is important to avoid and develop treatments of these diseases. Several small molecules (e.g. dihydropyridines and phenylalkylamine) have been identified and designed to modulate the activity of CaV1.2. Yet, their mode and site of action within the CaV1.2 channel are still unclear. In order to understand how these drugs interact with CaV1.2, a detailed three-dimensional structure of the human CaV1.2 channel is necessary. However, such structures have not been resolved yet.
  Toward this goal, this thesis employed computational molecular modeling techniques to model the transmembrane 1-subunit three-dimensional (3D) structure of the open and closed CaV1.2 channel. We used a combination of homology modeling and threading approaches along with classical and advanced molecular dynamics simulations to explore the conformational transitions between the closed and the open states of the channel. The ultimate goal was to predict the binding orientation and critical interactions for known CaV1.2 modulators.
  Our molecular dynamics simulations revealed many conformational changes in the pore and voltage-sensing domains of the CaV1.2 channel. The mode-of-binding of Amlodipine, Diltiazem, and Verapamil were also identified to the atomic level. Our binding affinity calculations suggest that both Amlodipine and Verapamil have a high potential to block the CaV1.2 channel. The conformational dynamics and the interactions reported from our binding mode analysis will be useful for understanding the structure-function-dynamic relationship in the CaV1.2 channel and guiding future drug design efforts.

• Subjects / Keywords

  • Cardiac Disease
  • CaV1.2
  • Molecular dynamics
  • Voltage-gated calcium channel
  • Dihydropyridine

• Graduation date

  Fall 2019

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/r3-9n8v-b693

• License

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