Sosnick Lab at The University of Chicago


Sosnick news


Sosnick Lab in Scientific American!


Biotech's First Musical Instrument Plays Proteins Like Piano Keys

Posted on Spet. 5th, 2013

New Paper in Biophysical Journal





Investigating Models of Protein Function and Allostery With a Widespread Mutational Analysis of a Light-Activated Protein

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Abstract
To investigate the relationship between a protein’s sequence and its biophysical properties, we studied the effects of more than 100 mutations in Avena sativa light-oxygen-voltage domain 2, a model protein of the Per-Arnt-Sim family. The A. sativa light–oxygen–voltage domain 2 undergoes a photocycle with a conformational change involving the unfolding of the terminal helices. Whereas selection studies typically search for winners in a large population and fail to characterize many sites, we characterized the biophysical consequences of mutations throughout the protein using NMR, circular dichroism, and ultraviolet/visible spectroscopy. Despite our intention to introduce highly disruptive substitutions, most had modest or no effect on function, and many could even be considered to be more photoactive. Substitutions at evolutionarily conserved sites can have minimal effect, whereas those at nonconserved positions can have large effects, contrary to the view that the effects of mutations, especially at conserved positions, are predictable. Using predictive models, we found that the effects of mutations on biophysical function and allostery reflect a complex mixture of multiple characteristics including location, character, electrostatics, and chemistry.

Posted on August 20th, 2013

Josiah Graduates! Congrats!

Josiah finished up his Ph.D. degree in Biochemistry and Molecular Biophysics!

Posted on July 25th, 2013

New Paper in PRL(Physical Review Letters)!


Simplified protein models: predicting folding pathways and structure using amino Acid sequences

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Abstract
Motivated by the relationship between the folding mechanism and the native structure, we develop a unified approach for predicting folding pathways and tertiary structure using only the primary sequence as input. Simulations begin from a realistic unfolded state devoid of secondary structure and use a chain representation lacking explicit side chains, rendering the simulations many orders of magnitude faster than molecular dynamics simulations. The multiple round nature of the algorithm mimics the authentic folding process and tests the effectiveness of sequential stabilization (SS) as a search strategy wherein 2° structural elements add onto existing structures in a process of progressive learning and stabilization of structure found in prior rounds of folding. Because no a priori knowledge is used, we can identify kinetically significant non-native interactions and intermediates, sometimes generated by only two mutations, while the evolution of contact matrices is often consistent with experiments. Moreover, structure prediction improves substantially by incorporating information from prior rounds. The success of our simple, homology-free approach affirms the validity of our description of the primary determinants of folding pathways and structure, and the effectiveness of SS as a search strategy.
Simplified protein models: predicting folding pathways and structure using amino Acid sequences

Posted on July 13th, 2013

Aashish Graduates! Congrats!

Aashish finished up his Ph.D. degree in Chemistry! What a lucky fellow.

Posted on Nov. 13th, 2012

New Paper in PNAS!





De novo prediction of protein folding pathways and structure using the principle of sequential stabilization
Abstract
Motivated by the relationship between the folding mechanism and the native structure, we develop a unified approach for predicting folding pathways and tertiary structure using only the primary sequence as input. Simulations begin from a realistic unfolded state devoid of secondary structure and use a chain representation lacking explicit side chains, rendering the simulations many orders of magnitude faster than molecular dynamics simulations. The multiple round nature of the algorithm mimics the authentic folding process and tests the effectiveness of sequential stabilization (SS) as a search strategy wherein 2° structural elements add onto existing structures in a process of progressive learning and stabilization of structure found in prior rounds of folding. Because no a priori knowledge is used, we can identify kinetically significant non-native interactions and intermediates, sometimes generated by only two mutations, while the evolution of contact matrices is often consistent with experiments. Moreover, structure prediction improves substantially by incorporating information from prior rounds. The success of our simple, homology-free approach affirms the validity of our description of the primary determinants of folding pathways and structure, and the effectiveness of SS as a search strategy.

Posted on Sept. 10th, 2012

Jack Skinner joins the Lab





Jack Skinner joins the lab as a Post-Doc coming from Walter Englander's lab at UPenn where he studied the conformational states of the MAD protein using Hydrogen Exchange.

Posted on Feb 22nd 2012

Alex "Frenchy" or "Frenchinald" French joins the lab





Alex French joins the Sosnick lab as a Ph.D. student in Biochemistry. He hopes to perfect his high kicks and pokemon skills among other things.

Posted on Sept 2011

Tobin Named Chair of Biochemistry




Congratulations to Tobin being named the Chair of the Biochemistry department.

Posted on August 5th 2011

Mia joins the Lab

Tobin, Aashish and Mia working hard

Posted on June 28th 2011

Tobin and ZZ in the Lab

It is not rare for Tobin to be in and around the lab but we had to take this picture so everyone could understand how excited Tobin becomes when he gets to wear a face shield!

Posted on December 7th, 2009

Welcome to the lab

located at The University of Chicago

The over-all goal of our research program is to understand how complex biological molecules adopt their functional, 3-dimensional conformations: The Protein and RNA Folding Problem. These synergistic studies, both experimental and computational, are based on the premise that rigorous and innovative studies of basic processes have broad implications in many areas of biological research. The folding process has considerable biological significance while posing a tremendous intellectual challenge. Beyond aiding in the prediction of structure from sequence, the relevance of folding studies is underscored by the involvement of misfolded conformers in a variety of human diseases and the role of “natively-unfolded” proteins in regulation, recognition, and binding. From the RNA standpoint, recent discoveries of the diverse roles structural RNAs play in gene expression, such as riboswitches, illustrate the importance of understanding their dynamics and folding as well. Other classes of non-coding RNAs are likely to be found with new regulatory roles.