Office: Proteomics 208M
Mail: Chemistry & Chemical Biology, 610 Taylor Road, Piscataway, NJ 08854
The Khare lab seek to gain a predictive understanding of enzymes using computational protein design and experimental characterization.
Design Principles of Molecular Recognition
The Khare lab will seek to understand the structural determinants of enzymatic specificity and reactivity using a combination of computational protein design and experimental characterization. Our goal is to develop a quantitative and predictive understanding of specificity at protein-ligand interfaces; this will inform various therapeutic and synthetic applications.
Natural selection has afforded highly efficient and selective biocatalysts and biosensors by exquisite optimization of the molecular recognition between proteins and ligands. In Nature, new enzymes and new substrate specificities arise by repurposing the catalytic machinery, i.e. protein functional groups and/or exogenous cofactors, of related existing enzymes by evolutionary sequence optimization. Sampling of new functions is achieved by accruing both point mutations and large-scale insertions/deletions (indels). On the computational side, we will develop methods to emulate this sampling -- especially large-scale indels -- to obtain new, even non-natural, activities and substrate specificities. On the experimental side, we will develop and use high-throughput assays to characterize libraries of designed proteins.
Fundamentally, these studies will help uncover the structural rules and evolutionary routes that dictate the emergence of new function. Practically, the ability to design novel catalysts and specificities will significantly aid in developing, for example, tailor-made therapeutics and bioremediation agents/pathways.
Honors and Awards
- Scholars for Tomorrow Fellowship, Graduate School, UNC-Chapel Hill (2001-2002)
- UNC-Chapel Hill Biophysics Graduate Trainee Award (2001-2002)
- Recipient of Honorary Graduate Stipend, Indian Institute of Technology Delhi (2000)
- S. D. Khare, F. Ding, and N. V. Dokholyan, "Folding of Cu, Zn superoxide dismutase and Familial Amyotrophic Lateral Sclerosis" J. Mol. Biol., 334: 515-525 (2003).
- S. D. Khare, M. Caplow, and N. V. Dokholyan, "The rate and equilibrium constants for a multi-step reaction sequence for the aggregation of superoxide dismutase in ALS" Proc. Natl. Acad. Sci. USA, 101: 15094-15099 (2004).
- J. Khatun*, S. D. Khare*, and N. V. Dokholyan, "Can contact potentials reliably predict stability of proteins?" J. Mol. Biol., 336: 1223-1238 (2004). *contributed equally
- R. D. S. Dixon, Y. Chen, F. Ding, S. D. Khare, K. C. Prutzman, M. D. Schaller, S. L. Campbell, and N. V. Dokholyan, "New insights into FAK signaling and localization based on detection of a FAT domain folding intermediate" Structure, 12: 2161-2171 (2004).
- B. Urbanc, L. Cruz, F. Ding, D. Sammond, S. Khare, S. V. Buldyrev, H. E. Stanley, and N. V. Dokholyan, "Molecular dynamics simulation of Amyloid- dimer formation" Biophys. J., 87: 2310-2321 (2004).
- S. D. Khare, K. C. Wilcox, P. Gong, and N. V. Dokholyan, “Sequence and structural determinants of Cu, Zn superoxide dismutase aggregation” Proteins: Struct. Funct. Bioinfo., 61: 617-632 (2005).
- S. D. Khare, F. Ding, K. N. Gwanmesia, and N. V. Dokholyan, “Molecular origin of polyglutamine-mediated aggregation in neurodegenerative diseases” PLoS Comp. Biol., 1: e30 (2005).
- S. D. Khare, and N. V. Dokholyan, "Common dynamical signatures of FALS-associated structurally-diverse Cu, Zn superoxide dismutase mutants" Proc. Natl. Acad. Sci. USA, 103: 3147-3152 (2006).
- S. D. Khare, M. Caplow, and N. V. Dokholyan, “FALS mutations in Cu, Zn superoxide dismutase destabilize the dimer and increase dimer dissociation propensity: a large-scale thermodynamic analysis” Amyloid, 13: 226-235 (2006).
- S. Barton, R. Jacak, S. D. Khare, F. Ding, and N. V. Dokholyan, "The length dependence of the polyQ-mediated protein aggregation" J. Biol. Chem., 282: 25487-25492 (2007).
- S. D. Khare, and N. V. Dokholyan, “Molecular mechanisms of polypeptide aggregation in human diseases” Curr. Protein Pept. Sci., 8: 573-579 (2007).
- R. Das, B. Qian, S. Raman, R. Vernon, J. Thompson, P. Bradley, S. Khare, M. D. Tyka, D. Bhat, D. Chivian, D. E. Kim, W. H. Sheffler, L. Malmström, A. M. Wollacott, C. Wang, I. Andre, and D. Baker, “Structure prediction for CASP7 targets using extensive all-atom refinement with Rosetta@home.” Proteins, 69: Suppl 8, 118-28 (2007).
- E. Weerapana, C. Wang, G. M. Simon, F. Richter, S. D. Khare, M. B. D. Dillon, D. A. Bachovchin, K. Mowen, D. Baker, and B. F. Cravatt, “Quantitative reactivity profiling predicts functional cysteines in proteomes” Nature, 468: 790-5 (2010).
- S. J. Fleishman, S. D. Khare, N. Koga, and D. Baker, “Restricted sidechain plasticity in the structures of native proteins and complexes” Protein Science, 20: 753-7 (2011).
- F. Richter, A. Leaver-Fay, S. D. Khare, S. Bjelic, and D. Baker, “De novo enzyme design using Rosetta3” PLoS One, 6: e19230 (2011).
- S. J. Fleishman, A. Leaver-Fay, J. E. Corn, E.-M. Strauch, S. D. Khare, N. Koga, J. Ashworth, P. Murphy, F. Richter, G. Lemmon, J. Meiler, and D. Baker, “RosettaScripts: a scripting language interface to the Rosetta macromolecular modeling suite” PLoS One, 6: e20161 (2011).
- S. D. Khare*, Y. Kipnis*, P. J. Greisen*, R. Takeuchi, Y. Ashani, M. Goldsmith, Y. Song, J. L. Gallaher, I. Silman, H. Leader, J. L. Sussman, B. L. Stoddard, D. S. Tawfik, and D. Baker, “Redesign of a mononuclear zinc metalloenzyme for organophosphate hydrolysis” Nature Chem. Biol., 8: 294-300 (2012). *contributed equally
- F. Richter, R. Blomberg, S. D. Khare, G. Kiss, A. P. Kuzin, A. J. Smith, J. L. Gallaher, Z. Pianowski, R. C. Helgeson, A. Grjasnow, R. Xiao, J. Seetharaman, M. Su, S. Vorobiev, S. Lew, F. Forouhar, G. J. Kornhaber, J. F. Hunt, G. T. Montelione, L. Tong, K. N. Houk, D. Hilvert, and D. Baker, “ Computational design of catalytic dyads and oxyanion holes for ester hydrolysis” Journal of the American Chemical Society, in press (2012).