Postdoctoral Fellowship: PRFB: Evolutionary determinants of protein biophysics

This action funds an NSF Postdoctoral Research Fellowship in Biology for FY 2025. The fellowship supports research and training of the fellow that will contribute to biology in innovative ways. Natural selection is the driving force of evolution.

However, while the tendency of selection is to increase fitness, new mutations and the random action of drift tend to decrease it, rendering selection less effective and producing populations that are not optimally fit. Although evolutionary outcomes depend on these dynamics, it is unknown how they affect the basic biology of life on earth, even at the molecular level of protein folding and function.

The present research thus investigates the consequences of mutation-selection-drift balance for protein stability, a fundamental aspect of protein biochemistry, illuminating the feedback between the dynamic process of molecular evolution and the underlying physical properties of evolving molecules. The results of this research will have implications for modeling, predicting, and directing evolutionary trajectories, important goals for designing and engineering more stable proteins for medical and industrial applications, as well as for understanding the evolutionary process.

The fellowship research will produce a large publicly available dataset, and the fellow will engage in outreach and serve as a dedicated research mentor to local community college and university students.

This research will determine the relationship between the thermodynamic stability of proteins (ΔGfold) and effective population size (Ne), as changing the latter tunes the evolutionary equilibrium between mutation, selection, and drift. Rhinovirus will be used as a model system, due to its small proteome, available sequencing data, and experimental tractability.

Mutational trajectories will be characterized in experimental, wild, and in silico populations of different census (and thus effective) population sizes and consequently different mutation-selection-drift equilibria. Stability and fitness effects of all rhinovirus 3C protease variants that arise in these systems will then be measured using multiplexed high-throughput methods, revealing how Ne shapes fitness and stability, and quantifying the relationship between these properties.

The Fellow will receive training in protein biophysics and virology, including technical training in cell culture as well as high-throughput and classical biophysical methods. The fellow will also organize scientific meetings and community-building events for the protein evolution field, and work to train the next generation of evolutionary biologists by providing supportive research experiences and ongoing mentorship to undergraduate students.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.