Molecular Mechanisms of Gating, Selectivity, and Transport in Membrane Channels and Carriers

Exchange of materials and information across biological membranes is one of the most fundamental and highly regulated processes in the biology of all living organisms. As lipid bilayers present a significant barrier to the transport of most materials, specialized membrane channels and carriers have been evolved to facilitate their transport across biological membranes. The water channel aquaporin (AQP) and the nucleotide transporter ADP/ATP carrier (AAC) are the focus of the research presented in this thesis. By facilitating water conduction across cellular membranes, AQPs play a significant role in water homeostasis in living cells. Of similar importance, AAC mediates the exchange of ADP and ATP across the mitochondrial membrane and is fundamental to energy production in eukaryotic cells. Using molecular dynamics simulations, the substrate selectivity, gas permeability and gating mechanism of AQPs, as well as the substrate binding and induced translocation in AAC, are investigated. Two AQPs from the same organism with different functionalities are used to identify key structural features determining the substrate selectivity of AQPs. Multiple sampling methodologies are applied to investigate the permeability of mammalian AQP1 and AQP4 to O2, CO2 and NO. Apart from water, these AQPs are found to provide pathways for gas molecules to cross biological membranes. Additionally, the phosphorylation-mediated gating of a plant aquaporin is investigated. Opening of the water channel upon phosphorylation is shown to result from coupled motion of a conserved cytoplasmic loop and a hydrophobic residue physically blocking the channel. In the last part of the thesis, insights into the nucleotide binding and translocation process mediated by AAC are presented. A rapid, spontaneous binding of ADP to AAC is revealed by multiple simulations, which is found to be driven by a strong electrostatic potential produced by the positively charged protein. The commonality and significance of this electrostatic potential in other mitochondrial carriers is also discussed.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biophysics and Computational Biology

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2015

Author dc:creator

• Wang, Yi

Contributors dc:contributor

• Tajkhorshid, Emad
• Schulten, Klaus J.

• Biophysics, General

Language dc:language

eng

Identifier

(MiAaPQ)AAI3347559

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/85475