The focus of our work centers on building models of unknown or partially unknown multi-protein systems involved in disease, as well as protein-ligand interactions capable of inhibiting/redirecting disease relevant conformations. Our aim is to develop clear, testable models for multi-protein and protein-ligand complexes, which are less readily characterized by more established structural biology methods. It is our hope that models developed using these IM-MS based approaches will enable the future generation of high-resolution structures through the integration of collision cross-section constraints (CCS) in tandem with other structural data and modeling techniques. We have chosen to focus our model building efforts within the areas of amyloid formation and protein aggregation diseases. Current targets of interest include: the Alzheimer’s disease associated amyloid-β peptides and hyper-phosphorylated Tau protein, in addition to the type 2 diabetes relevant Islet Amyloid Polypeptide (IAPP/Amylin) species. Our amyloid work is currently performed in collaboration with Ramamoorthy group (University of Michigan) and Lim group (Ulsan National Institute of Science and Technology).
Amyloid-β-Ligand Interactions with IM-MS
Interactions of aggregates, protein-protein, protein-peptide, and protein-small molecule can be studied with IM-MS. IM-MS datasets provide information on orientationally averaged CCS as well as stoichiometry of protein-ligand interaction. Using a ratio of intensities of apo and bound form, binding and dissociation constants can be calculated. Molecular dynamics (MD) simulations can be performed to generate structures of potential candidates for protein-ligand interaction using restraints from experimental data. In addition, site directed mutagenesis is capable of providing further mechanistic insights into these protein-ligand interactions.
For more details, please visit Soper, M. T., et al., Phys. Chem. Chem. Phys., 2013, 15 (23)
For a detailed summary of current work in this research area, please visit the publication site.