Laboratory of Molecular & Thermodynamic Modeling
Two projects are available with one in the biosciences and one in energy/environmental research.
The oxysterol binding protein (OSBP) and related proteins (ORP) are essential for eukaryotic and mammalian cell life. One function of the ORPs is to control the sterol levels and composition in lipid membranes. For yeast, the seven ORPs (or Osh genes) together control the sterol composition, and the deletion of all the Osh proteins results in cell death. The expression of ORP4 in human cancer cell lines and solid tumors suggests that ORP4 could be used as a tumor marker. However, it is unclear if ORPs are directly involved in the development of malignant cells. Recently, the crystal structure of Osh4 complexed with several sterols has been determined (Im, Y. J.; Raychaudhuri, S.; Prinz, W. A.; Hurley, J. H. Nature 2005, 437, 154).
A short-term goal of this project will be to investigate the bound state of Osh4 with cholesterol and 25-hydroxycholesterol. Molecular dynamics (MD) simulations of the solvated and bound Osh4 protein will be used to determine the atomic-level interactions that mediate this structural change. Additional and more complex methods, such as steered MD, may be needed to see conformational changes. Another goal is the study of the membrane bound state of the protein. Essential in this analysis is determining the surface area per lipid (A) as a function of sterol concentration in the membrane. Since this dependence is unknown, a model-free method for determination of A developed by Klauda et al. (BJ, 2006) will be used, where simulations and experiments are needed. Since there is a paucity of experimental data for surface area of the POPE (lipid important in bacteria) and PIP (important for attachement of the protein to membrane) lipids, x-ray diffraction experiments on mixed bilayers will be used. This experimental work performed by the student will be done in collaboration with Prof. John Nagle (Carnegie Mellon University). Then, MD simulations will be used to determine A based on the experimental data. Ultimately, a thermodynamically based equation of state for A as a function of cholesterol and lipid composition will be developed, so that one can determine A for any composition.
With the determined A, MD simulations of the unliganded conformation of Osh4 (apo-Osh4) will be used as a an initial structure of the protein and placed on the modeled membrane to promote the uptake of the sterol into the protein. The ultimate goal is determine the mechanism of sterol transport from the membrane to the protein. Together these short- and long-term simulations will advance our understanding of sterol transport in cells. It is expected that additional experimental/simulation work will be done on the hypothesized nature of other Osh proteins in to tether membranes and enhance sterol transport. This work will be in collaboration with Dr. Will Prinz (NIH/NIDDK).
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 three aspects; 1. thermodynamic stability of naturally occurring hydrates, 2. carbon dioxide hydrates, and 3. 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.
The safe and long term storage of industrial carbon dioxide is an important concern for the reduction of greenhouse gas emissions. CO2 hydrates offer a stable and long term means to store this greenhouse gas on the seafloor or in old petroleum wells. Important to sequestering this gas is understanding the stability and composition of the gas in hydrate form. For gas occupancy calculations, we will work in collaboration with an experimentalist, Prof. Werner Kuhs (Universität Göttingen, Germany). This will involve thermodynamic modeling and simulations of carbon dioxide hydrates.
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.