Rauscher, Sarah

Ph.D. | Assistant Professor | PhysicsComputational Biophysics

Contact Information

Phone: 
905 828 3805
Fax: 
905 828 5425
Room: 
DV4055
Mailing Address: 
3359 Mississauga Road
City: 
Mississauga
Province: 
Ontario
Postal Code: 
L5L 1C6
sarah

Research Areas:

Computational Biophysics

Research Profile:

rauscher research

        Intrinsically disordered proteins (IDPs) are abundant in all kingdoms of life and fulfill many critical biological functions. IDPs have been found, for instance, to regulate the cell cycle, transcription and translation, act as hubs in signalling networks, and maintain tight control over the locations of other proteins in the cell. IDPs also play roles, which are yet to be fully understood, in various diseases, such as Alzheimer’s, Parkinson’s, ALS, cancer, and AIDS. The tremendous biological importance of IDPs provides strong motivation for their detailed biophysical characterization.

            IDPs are still poorly understood relative to the wealth of structural information available for folded proteins. IDPs are notoriously difficult to study using experimental approaches. Moreover, on a fundamental level, their description poses formidable challenges: IDPs do not have a unique structure, but rather a structural ensemble consisting of many interconverting conformational states. Classical molecular dynamics (MD) simulations, with their empirical force fields, can be used to model the ensembles of IDPs, but there remain significant challenges in both statistical sampling and accuracy. Our previous research involved carrying out a systematic comparison of state-of-the-art force fields for the specific case of IDPs and developing an improved force field suitable for both IDPs and folded proteins (Rauscher et al. J. Chem. Theor. Comput. 2015, Huang et al. Nature Methods 2017). 

            The fact that accurate structural descriptions are still not available for many of the disordered proteins underlying human diseases severely impedes rational drug development. On a more fundamental level, we need a new structure-function paradigm that describes how the sequences of IDPs dictate their structural ensembles, and how the structural properties of IDPs give rise to their diverse cellular functions. Research in our group addresses this gap in our knowledge by obtaining atomistic descriptions of the structure and dynamics of IDPs. Comparison to experimental data is an integral part of our research program, not only to validate the structural ensembles, but also to improve parameters specifically for IDPs. The long-term goal of these studies is to develop a simulation methodology to obtain structural descriptions of IDPs as efficiently and accurately as possible. Methodological insights gained from studying specific IDPs will drive the continuous improvement of a robust simulation methodology for the study of IDPs in general. 

There are currently open positions in the group for post-doctoral fellows and graduate students. Interested candidates should send inquiries by email to sarah.rauscher@utoronto.ca.

Courses Taught: 

TBA

Publications

Recent 

1. Huang, J., Rauscher, S., Nawrocki, G., Ran,T., Feig, M., de Groot, B. L., Grubmüller, H., and MacKerell Jr., A. D. (2017) CHARMM36m: An Improved Force Field for Folded and Intrinsically Disordered Proteins. Nature Methods 14, 71-73 doi:10.1038/ NMETH.4067

2. Rauscher, S., Gapsys, V., Gajda, M. J., Zweckstetter, M., de Groot, B. L., and Grubmüller, H. (2015) Structural Ensembles of Intrinsically Disordered Proteins Depend Strongly on Force Field: A Comparison to Experiment. Journal of Chemical theory and Computation 11, 5513−5524. doi: 10.1021/acs.jctc.5b00736

3. Naqvi, A., Rauscher, S., Rousseau, D. and Pomès, R. (2014)  e Conformational Ensemble of the βÔÇÉCasein Phosphopeptide Reveals Two Independent Intrinsically Disordered Segments. Biochemistry 53, 6402−6408. doi: 10.1021/bi500107u

4. Neale, C., Madill, C. Rauscher, S., and Pomès, R. (2013) Accelerating Convergence in Molecular Dynamics Simulations of Solutes in Lipid Membranes by Conducting a Random Walk along the Bilayer Normal. Journal of Chemical theory and Computation 9, 3686–3703. doi: 10.1021/ct301005b

5. Rauscher, S. and Pomès, R. Structural Disorder and Protein Elasticity. In Fuzziness: Structural Disorder in Protein Complexes, edited by Peter Tompa and Monika Fuxreiter. Austin/New York: Landes Bioscience/Springer Science & Business Media, 2012:159-183. doi: 10.1007/978-1-4614-0659-4_10.

6. Seo, M., Rauscher, S., Pomès, R., and Tieleman, D. P. (2012) Improving Internal Peptide Dynamics in the Coarse-Grained MARTINI Model: Toward Large-Scale Simulations of Amyloid- and Elastin-like Peptides. Journal of Chemical theory and Computation 8, 1774–1785. doi: 10.1021/ct200876v

7. Li, G., Rauscher, S., Baud, S., and Pomès, R. (2012) Binding of Inositol Stereoisomers to Model Amyloidogenic Peptides. Journal of Physical Chemistry B 116, 1111-1119. doi: 10.1021/jp208567n

8. Nikolic, A., Baud, S., Rauscher, S. and Pomès, R. (2011) Molecular mechanism of β- sheet self-organization at water-hydrophobic interfaces. Proteins 79, 1-22. doi: 10.1002/prot.22854

9. Rauscher, S. and Pomès, R. (2010) Molecular Simulations of Protein Disorder. Biochemistry and Cell Biology 88, 269-290. doi: 10.1139/o09-169