Dissecting folding dynamics of biopolymers across scales - from single molecules to cells

My group is interested in understanding the folding and structural dynamics of proteins and RNAs. We are using single-molecule manipulation with optical tweezers to dissect folding pathways and resolve structural dynamics. To provide biological context, we are complementing these high-resolution measurements with cellular assays. Here, I will present work in two research areas: (1) Large, multi-domain proteins begin to fold during their synthesis by the ribosome. We are dissecting the co-translational folding pathway of a kinetically hyperstable protein, phosphoglycerate kinase (PGK). We find that the ribosome stabilizes a co-translational folding intermediate, catalyzing formation of the hyperstable native structure. (2) Trinucleotide repeat expansions cause several neurodegenerative disorders. Recently, it was discovered that repeat-containing mRNAs directly contribute to cellular toxicity. Using optical tweezers, we find that huntingtin mRNAs with expanded repeat regions exhibit ‘stick’slip’ unfolding that facilitates aggregation into cytotoxic species, providing a mechanistic underpinning of RNA toxicity.