Protein Folding

Protein Folding

Protein Folding

We are interested in characterizing the general principles that govern protein folding. Despite being a long studied problem, many questions remain unresolved, for example the physical folding events that dictate the pathway as well as a concise understanding of the origins of the cooperative protein folding.

Our studies are consistent with the principle of Sequential Stabilization - that protein folding is a series of smaller folding events described by the concurrent formation of secondary and tertiary structure, e.g. a turn of helix forms which buries hydrophobic surface area. Furthermore, proteins fold through transition states adopting very native-like topologies.


  • Many small proteins fold in a cooperative fashion so that only the native state and unfolded state populate. We can deduce characteristics of the transition state by connecting changes in the folding kinetics with specific structural stabilizations. To this end, we have characterized the folding transition states using psi analysis to determine the rate limiting step of formation. The TSEs of several proteins with varying degrees of topology may be described as having a high degree of the native topology (which is not the same as native-like structure).
  • From these TSE studies, we have proposed a general rule, "The 70% Rule", i.e. proteins fold through transition states that adopt ~70% of the native state topology, as definded by the relative contact order.
  • Other studies of protein folding have utilized hydrogen exchange methods to detect hidden intermediates on the folding landscape that do not necessarily populate thermodynamically.

Z.P. Gates*, M.C. Baxa*, W. Yu, J.A. Riback, H. Li, B. Roux, S.B.H. Kent, T.R. Sosnick, "Perplexing cooperative folding and stability of a low-sequence complexity, polyproline 2 protein lacking a hydrophobic core" Proc Natl Acad Sci U S A 114 (2017) 2241-6.

W. Yu, M.C. Baxa, I. Gagnon, K.F. Freed, T.R. Sosnick, "Cooperative folding near the downhill limit determined with amino acid resolution by hydrogen exchange" Proc Natl Acad Sci U S A 113 (2016) 4747-52.

M.C. Baxa, W. Yu, A.N. Adhikari, L. Ge, Z. Xia, R. Zhou, K.F. Freed, T.R. Sosnick, "Even with nonnative interactions, the updated folding transition states of the homologs Proteins G & L are extensive and similar" Proc Natl Acad Sci U S A 112 (2015) 8302-7.

J.J. Skinner, W. Yu, E.K. Gichana, M.C. Baxa, J.R. Hinshaw, K.F. Freed, T.R. Sosnick, "Benchmarking all-atom simulations using hydrogen exchange" Proc Natl Acad Sci U S A 111 (2014) 15975-80.

T.Y. Yoo, A. Adhikari, Z. Xia, T. Huynh, K.F. Freed, R. Zhou, T.R. Sosnick, "The folding transition state of protein L is extensive with nonnative interactions (and not small and polarized)" J Mol Biol 420 (2012) 220-34.

T.R. Sosnick, D. Barrick, "The folding of single domain proteins--have we reached a consensus?" Curr Opin Struct Biol 21 (2011) 12-24.

M.C. Baxa, K.F. Freed, T.R. Sosnick, "Psi-constrained simulations of protein folding transition states: implications for calculating φ" J Mol Biol 386 (2009) 920-8.