The long-term objective of this research project is to develop circularly polarized luminescence (CPL) as a tool for enantioselective recognition of biomolecules and for investigating chiral structures in metal-containing biomolecular systems. Molecular chirality-the property whereby two mirror images of a molecule cannot be superimposed on each other-is crucial to modern drug research. While the difference between chiral structures may seem trivially small, the slight change in the compounds'three-dimensional structure profoundly alters the given compound's interaction with its surroundings. For example, in the 1960s, racemic thalidomide was widely used to treat morning sickness. One of the enantiomers was effective at reducing morning sickness, but unfortunately the drug's other enantiomer caused birth defects. For this reason, it is easy to understand why single-enantiomer drugs are attractive, and researchers are looking at them as possible treatments for cancer, cardiovascular disease, and central nervous system (CNS) defects. In 2009, estimates suggest that enantiopure drugs will produce $15 billion in revenue. The central hypothesis of this proposal is that CPL is an advancement over the common circular dichroism (CD) method due to its superiority in sensitivity, reliability, ease of use, and minimal sample preparation. Of special importance is that our methodological refinement of directly and selectively exciting the lanthanide(III) ion (Ln(III) = Eu, Tb) will increase discrimination between luminescent sites, making interpretation easier (i.e. CPL will reflect the time- averaged local helicity around the Ln(III) ion). Of special interest is the importance of using CPL for selectively studying only luminescent chromophores present in the systems of interest;CD, in contrast, is affected by most chromophores and/or equilibrium mixtures in an additive manner. More specifically, the study will (1) investigate the sensitivity and selectively of CPL spectroscopy used as an analytical tool for enantioselective recognition of biomolecules such as amino acids, (2) examine the effectiveness of CPL spectroscopy as a probe into the existence of chiral lanthanide structures and as an indicator of changes in the chiral structures, and (3) demonstrate the importance of using europium(III) CPL spectroscopy to understand the relationships between the chiral structures of proteins and their ability to bind metal ions (i.e. Ca(II), Mg(II)) where these metal ions are substituted by Eu(III) ions.
With the knowledge that metal-binding proteins may account for as many as 40% of all proteins, this research field has gained a considerable interest and is still growing with the continuous discovery of new processes and functions of this class of proteins. Of special importance is to understand the function of the spectroscopically silent alkaline earth divalent cations Mg(II) and Ca(II) in many biological processes (i.e. enzyme activation, nucleic acid stabilization, muscle contraction, secretion, or synaptic transmission). On the other hand, the study of enantiomeric recognition of biological substrates is an ongoing active research because it can provide valuable information concerning molecular recognition mechanisms in biological materials.
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