Laboratory of Molecular & Thermodynamic Modeling
Three projects are available: one energy/environmental research project and two biomolecular research projects.
Gas hydrates (clathrates) are a solid network of water, forming cavities that encapsolates gas molecules. These are commonly found in pipelines and can plug the flow of natural gas, but also exist in nature within permafrost or the seafloor. Previous work has focused on developing a thermodynamic model for predicting the equilibrium pressures (or temperatures) of gas hydrates. This thermodynamic model along with a mass transfer model for methane hydrates in the seafloor suggests that there are three orders of magnitude more methane in hydrated form than in conventional global reserves. These results also have huge implications for an alternate source of natural gas reserves within the U.S. to reduce dependency on foreign energy sources.
This project on gas hydrates has two aspects; thermodynamic stability of naturally occurring hydrates and hydrogen storage. The crystal structure of hydrates depends on the composition of natural gas and thermal conditions. There are three known structures (sI, sII and sH) of hydrates, but there is limited thermodynamic modeling of the sH hydrate. This hydrate form is found in regions with heavier hydrocarbons and has been discovered recently in situ from the Cascadia margin (Lu et al. Nature. 2007, 445, 303). The goal of this portion of the project is to develop a thermodynamic model for sH hydrates based on my past work (Klauda & Sandler. Chem. Eng. Sci. 2003, 58, 27). Ultimately, this work will be important in future exploration and drilling for fossil fuels in the seafloor. Collaborations with Prof. Shiang-Tai Lin (National Taiwan University) and Prof. E. Dendy Sloan (Colorado School of Mines) involve using models to predict local hot spots for gas hydrates for oil companies to begin drilling for this alternate source of natural gas. This will involve thermodynamic and mass transfer modeling of various sources of natural gas from in situ conversion of organic matter to deeper thermogenic sources. The influence hydrates have on greenhouse emissions to the atmosphere and the overall carbon cycle will also be studied.
The final portion of this project involves the use of hydrates to store molecular hydrogen in an inert form and at ambient conditions. Although H2 can form hydrates in pure form, the pressures required for stability are enormous (>200 MPa). Binary hydrates with compounds such as tetrahydrofuran (THF) reduce the pressure issue but are limited in the wt% of storage. Moreover, THF is volatile and would contaminated the desired pure hydrogen gas phase. For this work, sH hydrates and semi-clathrate hydrates (Chapoy et al. JACS. 2007, 129, 746) will be studied to determine the feasibility of hydrates for H2 storage.
Over the past couple of years computational power has reached the point that we can go beyond the basic model systems of a single component membrane. However, nearly all computational studies of membranes involve at most two to three lipid components. My lab in collaboration with Prof. Wonpil Im’s lab at the University of Kansas has been the first to simulate at “realistic” yeast membrane of six components (Jo. et al. BJ. 2009, 97, 50). These models are essential for studies on intracellular cholesterol transport, membrane embedded proteins that result in drug resistant bacteria, studies of genetic causes for cataracts, etc. Moreover, a freely available website that contains equilibrated membranes of single-celled organisms to those in humans would be beneficial for the scientific community.
In this project, one of our aims is to expand a web-based tool (CHARMM-GUI) to allow for development of bilayers with varying lipids and proteins, so non-expert scientists can begin to use this valuable tool in their research (collaboration with Prof. Im’s lab). Originally the focus of this website was to setup simulations of transmembrane proteins in an explicit pure bilayer. We will continue to expand this to allow for combination of various lipids to form biomembranes. This will require simulations of various membrane models to develop a set of lipid conformations utilized by CHARMM-GUI. Ultimately, we also aim to understand the complex interaction between lipids that results in phase changes and various structural properties. For example, cholesterol has been generally classified as a molecule that condenses the molar volume of a bilayer, but recent experimental work suggests this is not entirely universal. Therefore, our studies would be beneficial in obtaining a more physically-based understanding of mixed biomembranes.
The initial studies on simple mixtures of lipid biomembranes will lead to research on membranes of biological organisms. Initial focus will be on models for the ocular lens membranes and organelle membrane models of yeast. The ocular lens is a unique membrane in that it contains a high concentration of cholesterol, i.e., at least 50%. These membranes result in very different properties compared to other membranes in the body. Beyond a fundamental science understanding, model ocular lens membranes will be important in studying genetic causes for cataracts that involve an inactive or insoluble membrane protein that transports water. Also important is the varying concentrations of lipids within a cell. The plasma membrane (outer most membrane) and endoplasmic reticulum membranes each have largely different concentrations of saturated lipids and various lipid head groups. These differences appear to be important in cholesterol transport from the synthesis source (ER) to the plasma membrane.
An important class of transmembrane proteins is the secondary active transporters that control the concentrations of certain molecules within a cell. These transporters couple the chemical gradient or movement of ions, such as H+ or Na+, with the movement of a solute and are expressed in all species from single-celled organisms to mammals. These proteins are involved in transporting many types of small molecules that are important for the cell to introduce or expel, e.g., ions, hydrophobic molecules, antibiotics, neurotransmitters, nutrients, and small peptides. Certain secondary active transporters are known to control the levels of antibiotics in bacteria and can lead to resistance of bacteria to certain drugs. Moreover, this class of proteins is extremely important in the human neurological system in that proteins control the release neurotransmitters.
Although understanding the transport mechanism for secondary active transporters is important, there is limited structural data available from x-ray diffraction. Moreover, proteins with known crystal structures only have structures of a single conformation. In other words, structural changes between the known protein conformation to states open to the periplasm or cytoplasm or are not well understood. It is our aim to utilize molecular simulation methods to obtain such structures and completely describe the transport cycle of certain membrane proteins. For this, we will use a method developed in my group IM-EX MS (implicit-explicit membrane simulation) to cross transition states and obtain unknown protein structures. Lactose permease, a sugar transporter of E. coli, will be used to further test this method because ample experimental data is available in Dr. Ron Kaback’s lab. This method will be used to study homologues of neurotransmitter symporters (vSGLT/LeuT). The ultimate goal is to give structural biologists a way to determine protein structures of unknown conformations based on a single known state.
In addition to further developing a method to predict protein structure, we aim to study molecular-level transport of drugs and other substrates. For example, secondary active transporters that are important in drug resistant bacteria (antibiotics are pumped out of the cell fast that they enter) require specific antibiotic-protein interactions. Determining the protein residues that are important in this transport cycle may lead to the ability to design drugs that effectively kill the organism without being expelled by these proteins.