Author ORCID Identifier

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

Year of Publication

2019

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Arts and Sciences

Department

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)

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