Chemistry and Biochemistry Seminar- Angel Martí, PhD
Molecular Binding, Energetics, and Stereochemical Effects in Supramolecular Amyloid Fibrils: Implications for Alzheimer’s Disease and Functional Amyloids
The Department of Chemistry and Biochemistry is pleased to invite you to an upcoming seminar featuring Angel Martí, PhD, from Rice University. He will be presenting his research in a talk titled: “Molecular Binding, Energetics, and Stereochemical Effects in Supramolecular Amyloid Fibrils: Implications for Alzheimer’s Disease and Functional Amyloids." Food will be served.
This event is approved for 1 Compass point.
SPEAKER
Angel Martí, PhD
Professor of Chemistry, Bioengineering, and Materials Science and NanoEngineering
Chair, Department of Chemistry
Rice University
ABSTRACT
The aggregation of Amyloid-β (Aβ) into insoluble fibrillar structures is linked to the onset of Alzheimer’s disease. Understanding the thermodynamics of how small molecules interact with these fibrils is essential for developing diagnostic PET tracers and therapeutic inhibitors, as well as for understanding how molecular entities that bind to amyloid plaques in the brain modulate pathogenicity. Quantitative analyses of the interactions between Aβ fibrils and ligands, including dissociation constant (K d) and binding stoichiometry (n), are crucial. However, the strong mathematical correlation between K d and n presents a fundamental challenge in their determination. In standard single-curve fitting, this dependency often leads to multiple solutions to the equation that describe the data equally well, resulting in significant ambiguity, particularly when the exact concentration of available binding sites is unknown. To address this, we have developed a robust analytical methodology that uses simultaneous global fitting of two independent variable-binding assays. By linking these datasets, we effectively “break” parameter correlations, enabling precise, unambiguous determination of K d and n. We demonstrate the power of this approach by studying the binding of ruthenium(II) dipyridophenazine complexes to Aβ fibrils. Our results extend beyond amyloid science as we show this global fitting model is uniquely suited for studying other periodic biopolymer systems characterized by heterogeneous binding landscapes, such as calf thymus DNA (ct-DNA). Using the described methodology, we will elucidate the energetics of ruthenium complexes binding to Aβ fibrils. To further explore molecular binding at the surface of Aβ fibrils, we investigated stereochemical effects in the binding of ruthenium dipyridophenazine complexes by determining K d and n for different enantiomers. Stereochemical effects were further examined by circular dichroism (CD) spectroscopy and high-level Quantum Mechanics/Molecular Mechanics (QM/MM) calculations. By providing a more rigorous mathematical foundation for biopolymer assays, this research facilitates the rational design of high-affinity ligands and offers a clearer window into the molecular surface of protein aggregates.