Moseley Laboratory Research Interests
Develop computational methods for analyzing and interpreting biological and biophysical data that:
- Leverage relevant information from public scientific databases.
- Integrate system-wide analyses across omics-level datasets.
Automated Analysis Tools for Magic Angle Spinning Solid State NMR Protein Resonance Data
Membrane proteins are essential for many biological functions. They comprise roughly one third of all sequenced genomes, and represent 70% of all current drug targets. However, fewer than 500 of the ~58,000 protein structure entries in the worldwide Protein Data Bank (PDB) involve integral membrane proteins as of June 2009. This is because they are difficult to crystallize for x-ray crystallographic studies and difficult to solubilize for solution nuclear magnetic resonance (NMR) studies. Magic-angle spinning solid-state NMR (MAS SSNMR) represents a fast developing experimental method that has great potential to provide structural and dynamics information of membrane proteins without the sample limitations of other techniques. We are developing automated analysis tools that will aid in the analysis of SSNMR data and specifically tailored for SSNMR data from membrane protein samples. Specifically our lab is focusing on developing and testing algorithms that will automate all analysis steps from raw SSNMR spectral data to protein resonance assignments for uniformly 13C/15N-labeled membrane proteins. This development will provide necessary analysis tools for expansion of MAS SSNMR and its application to membrane proteins into the broader biological community.
Automated Analysis and Prediction of Metal-Ion Coordination in Metalloproteins
Zinc ions bound to proteins serve a wide variety of catalytic, structural, and signal transduction purposes in biological systems. Zinc is the only metal ion seen in all six classes of enzymes. Iron and zinc are the most abundant trace elements in the human body. Roughly 2800 human proteins are predicted to be zinc-binding which equates to 10% of the human genome. Change in zinc trafficking is now associated with a variety of diseases, including Alzheimer’s, Parkinson’s, type 2 diabetes, and pathological conditions related to neural and myocardial ischemia. Recently, great strides were made in predicting zinc-binding from 3D structure and from sequence across many genomes. However, verification, classification, and sequence annotation of zinc-binding lags behind. Using nuclear magnetic resonance (NMR) chemical shift data, we have developed an analysis for identifying Zn-ligated cysteine residues and verifying zinc-binding.
Systems Biochemistry Approach to Metabolomic Analysis
With the improvements in mass spectrometry and nuclear magnetic resonance, there is an explosion of metabolomics data being collected on a variety of cells and tissue associated with human diseases, especially cancer. The weight of the data requires the development of automated analysis methods that are truly robust. We are developing ways to combine analyses of NMR and mass spectrometry metabolomics data that can lead to robust metabolite analysis. Such new methods will allow a wealth of metabolomics data to be brought into the analysis and deconvolution of metabolic pathways. For example, we are developing a combined simulated annealing and genetic algorithms method called GAIMS to analyze NMR and FT-ICR-MS isotopomer data of uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) and uridine diphospho-N-acetylgalactosamine (UDP-GalNAc) extracted from tissue culture grown on 13-C enriched media. Both metabolites are used in O-glycosylation of proteins which serves cellular regulatory roles in nutrient sensing, protein degradation, and gene expression. We are applying these analyses to cancer tissue cultures treated with potential cancer chemoprevention agents to better understand how these agents change cancer cell metabolism.
- 21 Aug 2008