Multi-Scale Computational Studies of Calcium (Ca²⁺) Signaling

Author

Bin Sun, University of KentuckyFollow

Author ORCID Identifier

https://orcid.org/0000-0003-2583-4493

Date Available

12-13-2019

Year of Publication

2019

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Arts and Sciences

Department/School/Program

Chemistry

First Advisor

Dr. Peter M. Kekenes-Huskey

Abstract

Ca²⁺ is an important messenger that affects almost all cellular processes. Ca²⁺ signaling involves events that happen at various time-scales such as Ca²⁺ diffusion, trans-membrane Ca²⁺ transport and Ca²⁺-mediated protein-protein interactions. In this work, we utilized multi-scale computational methods to quantitatively characterize Ca²⁺ diffusion efficiency, Ca²⁺ binding thermodynamics and molecular bases of Ca²⁺-dependent protein-protein interaction. Specifically, we studied 1) the electrokinetic transport of Ca²⁺ in confined sub-µm geometry with complicated surfacial properties. We characterized the effective diffusion constant of Ca²⁺ in a cell-like environment, which helps to understand the spacial distribution of cytoplasmic Ca²⁺. 2) the association kinetics and activation mechanism of the protein phosphatase calcineurin (CaN) by its activator calmodulin (CaM) in the presence of Ca²⁺. We found that the association between CaM and CaN peptide is diffusion-limited and the rate could be tuned by charge density/distribution of CaN peptite. Moreover, we proposed an updated CaM/CaN interaction model in which a secondary interaction between CaN’s distal helix motif and CaM was highlighted. 3) the roles of Mg²⁺ and K⁺ in the active transport of Ca²⁺ by sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) pump. We found that Mg²⁺ most likely act as inhibitor while K⁺ as agonist in SERCA’s transport process of Ca²⁺. Results reported in this work shed insights into various aspects of Ca²⁺ signaling from molecular to cellular level.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2020.028

Funding Information

Maximizing Investigators’ Research Award (MIRA) (R35) from the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH) under Grant R35GM124977 (09/01/17-08/31/22)

Recommended Citation

Sun, Bin, "Multi-Scale Computational Studies of Calcium (Ca²⁺) Signaling" (2019). Theses and Dissertations--Chemistry. 118.
https://uknowledge.uky.edu/chemistry_etds/118