Protein Folding and Design


The unifying theme of this subgroup is the quest to understand physical and evolutionary principles that govern folding of proteins into their unique biologically active structure. We developed a variety of approaches - from analytical theory of random and evolutionary selected heteropolymers to lattice and other simplified models to all-atom simulations with fully transferable potentials. Our group discovered universal physical requirements for polypeptide chains to fold into unique structure (energy gap criterion), uncovered universal kinetic mechanism of protein folding that dominates present understanding of protein folding kinetics (nucleation scenario) and showed deep connection between physical mechanism of protein folding and evolutionary selection of sequences (phenomenon of ''Conservation of Conservation''). More recently we developed new approaches to high-resolution protein folding that, for the first time, allowed all atom ab initio folding of structurally diverse proteins into their native conformations that are global minima of energy. This is achieved due to development of new fully transferable all-atom potential for protein folding. In the future we plan to build on these development to work towards complete understanding of protein folding mechanism(s) at atomic level of detail and fully automated methods to predict protein structure from sequences in ab initio simulations.

Recent publications from our group in this area:

  1. Ranganathan, S. & Shakhnovich, E.I. Dynamic metastable long-living droplets formed by sticker-spacer proteinsElife 9, e56159 (2020). Publisher's Version
  2. Razban, R.M. & Shakhnovich, E.I. Effects of single mutations on protein stability are Gaussian distributedBiophysical Journal (2020). Publisher's Version
  3. Bitran, A., Jacobs, W.M., Zhai, X. & Shakhnovich, E. Cotranslational folding allows misfolding-prone proteins to circumvent deep kinetic trapsProceedings of the National Academy of Sciences (2020). Publisher's Version
  4. Jacobs, W.M. & Shakhnovich, E.I. Accurate Protein-Folding Transition-Path Statistics from a Simple Free-Energy LandscapeThe Journal of Physical Chemistry B 122, 49, 11126-11136 (2018). Publisher's Version