Molecular modeling complements conventional experiments by providing atomistic details behind the structural dynamics of transport proteins and unraveling the complex relationships among their structures and functions. In this thesis, we use molecular modeling to study the Orai channel and ProP transporter. Orai proteins function as store-operated calcium channels in most eukaryotic cells and are particularly interesting due to their high calcium selectivity, low conductance and unusual pore structures. We present molecular dynamics simulations of two Orai multimers – hexamer and tetramer – and examine their structural dynamics. The results show that the Orai tetramer retains most of the structural features of the hexamer, while creating a more tightly-packed hydrophobic pore. We then present free energy calculations of ion permeation through these multimers. To test whether the Orai pore can be opened via helix rotation, the multimers with rotated pore-forming helices were also simulated. Our results demonstrate that helix rotation significantly lowers the energy cost of ion translocation along the Orai pore, regardless of multimeric state. What depends on stoichiometry is the Ca2+ selectivity versus Na+. When opened, the hexameric pore is better adapted to Ca2+ permeation, displaying changes in relative permeabilities that are consistent with calcium-selective currents. Interestingly, the opening of the hexamer barely makes a difference for the permeation of Na+ and K+ ions, while opening the tetramer almost completely removes the barrier for these ions. 
We also present our work on the E. coli ProP transporter, which pumps osmolytes into cells to prevent cellular dehydration as the cytoplasmic cation concentration increases. We built a homology model of the cytoplasmic C-terminal domain (CTD) of ProP that is implicated in osmosensing and performed molecular dynamics simulations to examine salt dependency in the CTD-membrane association. The salinity dependence of the CTD-membrane interaction does not arise from changing salt bridge patterns. In fact, it correlates with a decrease in membrane fluidity due to increasing salinity. 
To our knowledge, the studies presented here are the first computational work addressing the selectivity and permeation of Orai channels in two different multimeric states, as well as building a model structure of the cytoplasmic domain of ProP.