Tobin SosnickSenior Fellow
My research program involves synergistic studies of protein and RNA folding. The program is based on the premise that rigorous and innovative studies of basic processes have broad implications in many areas of biological research. The growing appreciation of natively-unfolded proteins in regulation, recognition and disease underscores the relevance of folding to a large number of biological processes. Likewise, recent discoveries of the diverse role structured RNAs play in gene expression illustrate the importance of understanding their dynamics. In the past 7 years, we have learned to direct folding and dynamics of these biopolymers. We are now designing proteins and RNAs to control their structure and function. We have developed Psi-analysis, a widely applicable method that identifies the number and the contribution of folding routes. The method utilizes designed metal binding sites in conjunction with a new theory to analyze the accompanying non-linear Bronsted behavior. It has provided the most accurate description of a protein folding pathway yet obtained. We are also predicting structures of unfolded and native proteins through statistical-based analyses and by simulating folding pathways, taking advantage of our experimental results and an approach that dynamically integrates local and global information. In RNA folding, we generated atomic level models of intermediates and revealed the principles of tertiary RNA stability using homologous RNAs from mesophilic and thermophilic organisms. Our studies have led to the concept of thermodynamic and kinetic hotspots. These fundamental studies have helped us examine how RNAs may fold in the cell. We found that specific pausing by RNA polymerase alters RNA folding during transcription. We are now testing whether species-specific polymerase pausing assists RNA folding during transcription.