Applying to the Sosnick Group

UChicago is an excellent place for scientific research and training with a collaborative and interdisciplinary environment. We are always interested in creative and driven individuals who love science to join our group. If you would like to learn more about our research and possible opportunities, please contact Prof. Tobin Sosnick

Post-doctoral Position in Computational Protein Dynamics

The Sosnick group is seeking a qualified individual for a postdoctoral position in the study of protein dynamics using ultra-fast MD. The candidate will investigate protein folding mechanisms, IDPs & IDRs, protein-protein phase separation, and hydrogen exchange, depending on interest. The candidate will employ and advance Upside, our new MD package that can reversibly fold proteins in cpu-days without using fragments, homology or evolution [1,2]. Upside utilizes a number of unique features including rapid side chain packing that enables simulations with only 3 backbone atoms while retaining considerable detail to avoid side chain "rattling", which greatly slows standard all-atom methods. Parameter training is accomplished using Contrastive Divergence, a machine-learning method that can train all parameters simultaneously. The ready generation of Boltzmann ensembles allows for a wide range of computational studies of protein folding, dynamics, and binding. Experience in computation biophysics, computer science, programming, machine learning, statistics or related areas is highly preferred. Contact with CV and names of references.

[1] J.M. Jumper, K.F. Freed, T.R. Sosnick,"Trajectory-Based Parameterization of a Coarse-Grained Forcefield for High-Throughput Protein Simulation" bioRxiv:169326.

[2] J.M. Jumper, K.F. Freed, T.R. Sosnick,"Maximum-likelihood, self-consistent side chain free energies with applications to protein molecular dynamics" arXiv:1610.07277 [q-bio.BM].

Post-doctoral Position in Biophysics of Phase-Separation

Post-doctoral position in biophysics available to study protein phase separation in poly(A)-binding protein (Pab1), in collaboration with DA Drummond lab, also at UChicago. The individual will determine in molecular detail how Pab1 phase separates in response to physiological stress conditions, which is crucial for cell survival and growth [1, 2]. Studies of Pab1’s unique stress-triggered phase separation behavior will be conducted at multiple length scales, and investigate the influence of physiological RNA targets on phase separation. Experience in biophysics including NMR or hydrogen exchange techniques preferred. Contact with CV and names of references

[1] J.A. Riback*, C.D. Katanski*, J.L. Kear-Scott, E.V. Pilipenko, A.E. Rojek, T.R. Sosnick, D.A. Drummond,"Stress-Triggered Phase Separation Is an Adaptive, Evolutionarily Tuned Response" Cell 168 (2017) 1028-40.

[2] E.W. Wallace, J.L. Kear-Scott, E.V. Pilipenko, M.H. Schwartz, P.R. Laskowski, A.E. Rojek, C.D. Katanski, J.A. Riback, M.F. Dion, A.M. Franks, E.M. Airoldi, T. Pan, B.A. Budnik, D.A. Drummond,"Reversible, Specific, Active Aggregates of Endogenous Proteins Assemble upon Heat Stress" Cell 162 (2015) 1286-98.

Project Summary

Our studies aim to determine in molecular detail the mechanism(s) by which poly(A)-binding protein Pab1 phase-separates to form hydrogel assemblies during stress. Cellular stresses cause the evolutionarily conserved, putatively adaptive formation stress granules. Pab1 is a defining marker of stress granules, and Pab1’s phase separation precedes stress granule formation. Dysregulation of phase separation of multiple RNA-binding proteins is linked to pathological protein aggregation associated with major neurodegenerative disorders. The mechanism(s) of phase separation is an area of active inquiry. The key barrier has been a lack of tractable in vitro models of biologically relevant phase separation by an RNA-binding protein.

We have broken through this barrier. In recently published work, we have established that Pab1 phase-separates into hydrogel droplets in response to physiological stress conditions, and that interfering with hydrogel droplet formation disrupts budding yeast’s ability to survive thermal and starvation stress. No previously described system combines a stress-triggered phase separation process, phenotypic consequences during stress, and the ability to reconstitute phase separation at physiological concentrations and conditions. Pab1/poly(A)-binding protein is conserved across eukaryotes and is a core marker of stress granules, making it a promising model for determining the molecular basis of stress-induced phase separation. We will study Pab1’s phase separation at multiple scales, including the influence of RNA, using a combination in vitro and in vivo approaches to determine how this unique phase separation process is encoded.

We will test specific hypotheses, such as the involvement of electrostatic interactions between RNA-binding domains and hydrophobic interactions between IDRs, using mutational approaches combined with hydrogen exchange mass spectrometry (HX-MS), NMR, dynamic light scattering, and small-angle X-ray scattering. We will further develop a mesoscale assay which provides rich information about how Pab1 interactions influence the properties of the resulting assemblies (viscosity, nucleation versus growth, changes in phase) thought to contribute to its biological functions. The project combines the expertise of two complementary investigators. Sosnick brings his expertise in protein folding and chemistry while Drummond brings his extensive experience in Pab1 and stress biology.