CPOS Seminar: "Transient Oligomers of Neuropeptides as Drug Development Targets"

Speaker: Pritam Ganguly, Assistant Project Scientist, Department of Chemistry and Biochemistry, University of California, Santa Barbara

Neurodegenerative diseases affect millions worldwide, with protein aggregation playing a central role in their pathology. In this talk, I will present an overview of our research on the aggregation of neurologically relevant intrinsically disordered peptides implicated in neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS), Parkinson's, and Alzheimer's disease. I will highlight our drug development strategy, which targets peptide aggregation at early oligomeric stages. I will briefly introduce the molecular dynamics simulation methods we use to probe the structures of these transient oligomers. As a specific example, I will discuss our use of enhanced-sampling temperature replica-exchange molecular dynamics (t-REMD) simulations to investigate the structural dynamics of a 13-residue fragment of the TAR DNA-binding protein 43 (TDP-43_307–319), a peptide central to ALS pathology. This minimal fragment is capable of autonomous aggregation, forms the core of full-length TDP-43 fibrils, and is known to be neurotoxic, making it a promising therapeutic target. Next, I'll demonstrate how we leverage these oligomer structures, atomic interaction profiles, and solvation thermodynamics to screen drug candidates. In the final part of my talk, I will elaborate on the solvation thermodynamics framework we use to predict protein-drug interactions and highlight our recent efforts to develop thermodynamically consistent models that account for solvent effects on protein aggregation in biologically relevant mixed-solvent systems. This section will focus in particular on osmolytes such as trimethylamine N-oxide (TMAO) and urea, which are critical for osmotic stress regulation in marine organisms and are also implicated in human pathologies.