RUI: Developing Ion Mobility Mass Spectrometry Techniques for Determining the Structure and Mechanisms of Metal Ion Recognition & Redox Activity of Metal Ion Binding Oligopepti

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In this project, funded by the Chemical Structure, Dynamic & Mechanism B Program of the Chemistry Division, Professor Laurence Angel of the Department of Chemistry at Texas A&M University - Commerce is developing new classes of copper and zinc chelating peptides. Disruption of copper and zinc homeostasis is directly implicated in Menkes and Wilson's disease as well as cancers and neurological diseases, such as Alzheimer's and prion disease. Metal chelators are used in the treatment of these types of diseases. The project is well suited for the interdisciplinary training of students in support of the growing bioanalytical, proteomic, bioengineering, and biomedical workforce. Under-represented groups of undergraduate students, including first-generation college students, African-American, Hispanic, and female students, will be encouraged to join the research efforts. More technically, the solution-phase metal ion reactivity of alternative metal-binding peptides (AMBS) and methanobactin (mb-OB3b) is being examined by electrospray ionization ion mobility-mass spectrometry (IM-MS) and density functional theory (DFT). Ultraviolet-visible and fluorescence spectral techniques are being used to check for correlations across gas- and solution-phase analyses to answer the following questions: (1) Which solution-phase behaviors can be examined in the gas phase? (2) Does pH-dependent metal-ion binding result in positively or negatively charged complexes that reflect the solution-phase states? (3) Which sequence residues affect AMBS and mb-OB3b metal-ion binding? (4) Which dissociation mechanisms are involved in the collision-induced dissociation (CID) of AMBS and AMBS cationized by Zn(II) or Cu(I)? (5) Can the metal-ion coordination sites be identified using energy-resolved CID and IM-MS? (6) Can metal-ion displacement be monitored by IM-MS titrations and collision cross-section changes? (7) Can IM-MS analyses and theoretical collision cross-sections identify which type of coordination each metal ion prefers? (8) How do IM-MS, DFT, UV-Vis, and fluorescence findings correlate? The study could discover new reaction mechanisms and develop more effective IM-MS molecular analysis techniques, while moving toward the design of chelating agents for treating diseases related to metal-ion imbalance.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.