The Faculty

Focus

Protein & RNA folding, design & function, simulations & predictions

Education

Ph.D. Applied Physics, Harvard Univ. 1989; M.S. Applied Physics, Harvard Univ. 1986; B.A. Physics, Univ. of Calif., San Diego

Research Summary

My research program involves synergistic studies of protein and RNA folding, function and design, with both experimental and computational components. The research is based on the premise that rigorous and innovative studies of basic processes have broad implications in many areas of biological research. My experimental experience in protein folding, design, modeling, and biophysical methods provides an enormous benefit to our computational studies which heavily rely on the use of fundamental principles of protein folding. Since my Ph.D. in low temperature physics in 1989, I have entered many different biological fields and have made an impact in each area. These areas include delineating protein and RNA folding pathways, de novo structure prediction, design of light-triggered allosteric proteins, and RNA folding during transcription. My lab employs a range of experimental and computational methods including NMR, small-angle X-ray scattering, rapid mixing methods, hydrogen exchange, molecular dynamics and coarse-grain folding simulations. I am a very a strong believer in collaboration, having co-mentored 15+ students and post-doctoral fellows who produced 30+ papers in the last 10 years.

Selected Publications

Publications relevant to grant proposal (PMCID listed when possible)

1. Adhikari A, Freed KF, & Sosnick TR (in press) De novo prediction of protein folding pathways and structure using the principle of sequential stabilization. Proc. Natl. Acad. Sci. U S A. PMID: 23045636

2. Yoo TY, et al. (2012) Small-angle X-ray scattering and single-molecule FRET spectroscopy produce highly divergent views of the low-denaturant unfolded state. J. Mol. Biol. 418(3-4):226-236. PMID:22306460

3. Yoo TY, et al. (2012) The folding transition state of protein L is extensive with nonnative interactions (and not small and polarized). J. Mol. Biol. 420(3):220-234. PMCID: PMC3372659

4. Sosnick TR & Hinshaw JR (2011) How proteins fold. Science 334(6055):464-465. PMID: 22034424 (PMCID unavailable)

5. Shandiz AT, Baxa MC, & Sosnick TR (2012) A "Link-Psi" strategy using crosslinking indicates that the folding transition state of ubiquitin is not very malleable. Prot. Science 21(6):819-827. PMCID: PMC3403417

6. Baxa MC, Haddadian EJ, Jha AK, Freed KF, & Sosnick TR (in press) Context and Force Field Dependence of the Loss of Protein Back-bone Entropy upon Folding Using Realistic Denatured and Native State Ensembles. J. Am. Chem. Soc. 134(38):15929-36 PMCID: PMC3464005

7. Adhikari AN, et al. (2012) Modeling large regions in proteins: Applications to loops, termini, and folding. Protein Sci. 21(1):107-121. PMCID: PMC3323786

8. Sosnick TR & Barrick D (2011) The folding of single domain proteins--have we reached a consensus? Curr. Opin. Struct. Biol. 21(1):12-24. PMCID: PMC3039110

9. Zheng Z & Sosnick TR (2010) Protein vivisection reveals elusive intermediates in folding. J. Mol. Biol. 397(3):777-788. PMCID: PMC2838964

10. DeBartolo J, et al. (2009) Mimicking the folding pathway to improve homology-free protein structure prediction. Proc. Natl. Acad. Sci. U S A 106(10):3734-3739. PMCID: PMC2656149

11. Bosco G, Baxa M, & Sosnick T (2009) Metal binding kinetics of bi-Histidine sites used in Psi-analysis: Evidence for high energy protein folding intermediates. Biochemistry 48(13):2950-2959. PMCID: PMC3313835

12. Baxa MC, Freed KF, & Sosnick TR (2009) Psi-constrained simulations of protein folding transition states: implications for calculating Phi values. J. Mol. Biol. 386(4):920-928. PMCID: PMC2742336

13. Watters AL, et al. (2007) The highly cooperative folding of small naturally occurring proteins is likely the result of natural selection. Cell 128(3):613-624. PMID: 17289578

14. Meisner WK & Sosnick TR (2004) Barrier-limited, microsecond folding of a stable protein measured with hydrogen exchange: Implications for downhill folding. Proc. Natl. Acad. Sci. U S A 101(44):15639-15644.

15. Virtanen JJ, Makowski L, Sosnick TR, & Freed KF (2011) Modeling the Hydration Layer around Proteins: Applications to Small- and Wide-Angle X-Ray Scattering. Biophysical J. 101(8):2061-2069. PMCID PMC3192974