Chemistry and Biochemistry
Institute of Molecular Biology
University of Oregon
The evolution of kicking and screaming stochastic proteins
In the Harms lab, we study the interplay between the biophysical features of proteins and their evolution. Macromolecules exist as ensembles of interchanging conformations. Such dynamics are important for molecular function and regulation. I hope to convince you these ensembles also shape evolution. Using theoretical and computational approaches, we found that subtle changes in ensemble composition can profoundly alter the effects of future mutations. Using experiments on the lac repressor and an RNA riboswitch, we revealed that these predicted effects are detectable both in vitro and in vivo. Using phylogenetic reconstructions and experimental studies of the innate immune protein S100A9, we revealed that molecular ensembles have indeed shaped the historical evolution of natural proteins. We are currently working on computational models to both predict these effects for specific proteins and to detect bioinformatic signatures of this phenomenon in multiple sequence alignments. Together, this work is revealing an intimate connection between molecular ensembles—an inescapable biophysical feature of macromolecules—and how macromolecules evolve. Specifically: subtle, functionally invisible, changes to the energies of low-population conformations can open and close future mutational trajectories, thus dramatically altering evolutionary outcomes.
Host: Dan Raleigh
Refreshments following the seminar in room 110