Engineered biological systems, ranging from molecules with new functions to entire organisms, have tremendous practical importance; they can also fundamentally change how we ask questions about the biological principles of function and fitness. Our research aims to invent approaches to engineer new molecules that operate as predicted in biological contexts, and to utilize prediction and engineering to address fundamental questions on the relationship of molecular characteristics, cellular function and organismal fitness. To address the many current challenges in the field – from developing more predictive computational design methods to determining the requirements for function in cells – we combine concepts from computer science, physics, chemistry, mathematics, engineering and biology.
Latest Preprints
Glasgow A, Hobbs HT, Perry ZR, Marqusee S, Kortemme T. Ligand-induced changes in dynamics mediate long-range allostery in the lac repressor. 2021 bioRxiv https://www.biorxiv.org/content/10.1101/2021.11.30.470682v1
Mathy, CJP, Mishra P, Flynn JM, Perica T, Mavor D, Bolon DNA, & Kortemme T. Complete mutational mapping of a GTPase switch in vivo reveals novel allosteric regulation. 2022 bioRxiv https://doi.org/10.1101/2022.04.13.488230
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Selected Publications
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Krivacic C*, Kundert K*, Pan X*, Pache RA*, Liu L, Conchúir SO, Jeliazkov JR, Gray JJ, Thompson MC, Fraser JS, & Kortemme T. Accurate positioning of functional residues with robotics-inspired computational protein design. Proc Natl Acad Sci U S A, 2022;119(11), e2115480119.
Perica T*, Mathy CJP*, Xu J, Jang GΜ, Zhang Y, Kaake R, Ollikainen N, Braberg H, Swaney DL, Lambright DG, Kelly MJS, Krogan NJ, Kortemme T. Systems-level effects of allosteric perturbations to a model molecular switch. Nature. 2021 Oct 13:1-6.
Pan X, Thompson M, Zhang Y, Liu L, Fraser JS, Kelly MJS & Kortemme T (2020). Expanding the space of protein geometries by computational design of de novo fold families. Science 369(6507):1132-1136.
Thompson S, Zhang Y, Ingle C, Reynolds KA, Kortemme T. Altered expression of a quality control protease in E. coli reshapes the in vivo mutational landscape of a model enzyme. Elife. 2020 Jul 23;9:e53476.
Glasgow AA, Huang YM, Mandell DJ, Thompson M, Ritterson R, Loshbaugh AL, Pellegrino J, Krivacic C, Pache RA, Barlow KA, Ollikainen N, Jeon D, Kelly MJS, Fraser JS, Kortemme T. (2019) Computational design of a modular protein sense-response system. Science. 22;366(6468):1024-1028.
Kundert K, Lucas JE, Watters KE, Fellmann C, Ng AH, Heineike BM, Fitzsimmons CM, Oakes BL, Qu J, Prasad N, Rosenberg OS, Savage DF, El-Samad H, Doudna JA, Kortemme T. (2019) Controlling CRISPR-Cas9 with ligand-activated and ligand-deactivated sgRNAs. Nat Commun. 9;10(1):2127.
Hoersch D, Roh SH, Chiu W, Kortemme T. (2013) Reprogramming an ATP-driven protein machine into a light-gated nanocage. Nat Nanotechnol. 8(12):928-32.
Eames M, Kortemme, T. (2012). Cost-benefit tradeoffs in engineered lac operons. Science 336(6083): 911-915.
Kapp GT, Liu S, Stein A, Wong DT, Reményi A, Yeh BJ, Fraser JS, Taunton J, Lim WA, Kortemme T. (2012). Control of protein signaling using a computationally designed GTPase/GEF orthogonal pair. Proc Natl Acad Sci U S A. 109(14): 5277-82.
Mandell DJ, Coutsias EA, Kortemme T. (2009). Sub-angstrom accuracy in protein loop reconstruction by robotics-inspired conformational sampling. Nat Methods 6:551–552.
Smith CA, Kortemme T. (2008). Backrub-like backbone simulation recapitulates natural protein conformational variability and improves mutant side-chain prediction. J Mol Biol. 380(4):742-56.
Perica T*, Mathy CJP*, Xu J, Jang GΜ, Zhang Y, Kaake R, Ollikainen N, Braberg H, Swaney DL, Lambright DG, Kelly MJS, Krogan NJ, Kortemme T. Systems-level effects of allosteric perturbations to a model molecular switch. Nature. 2021 Oct 13:1-6.
Pan X, Thompson M, Zhang Y, Liu L, Fraser JS, Kelly MJS & Kortemme T (2020). Expanding the space of protein geometries by computational design of de novo fold families. Science 369(6507):1132-1136.
Thompson S, Zhang Y, Ingle C, Reynolds KA, Kortemme T. Altered expression of a quality control protease in E. coli reshapes the in vivo mutational landscape of a model enzyme. Elife. 2020 Jul 23;9:e53476.
Glasgow AA, Huang YM, Mandell DJ, Thompson M, Ritterson R, Loshbaugh AL, Pellegrino J, Krivacic C, Pache RA, Barlow KA, Ollikainen N, Jeon D, Kelly MJS, Fraser JS, Kortemme T. (2019) Computational design of a modular protein sense-response system. Science. 22;366(6468):1024-1028.
Kundert K, Lucas JE, Watters KE, Fellmann C, Ng AH, Heineike BM, Fitzsimmons CM, Oakes BL, Qu J, Prasad N, Rosenberg OS, Savage DF, El-Samad H, Doudna JA, Kortemme T. (2019) Controlling CRISPR-Cas9 with ligand-activated and ligand-deactivated sgRNAs. Nat Commun. 9;10(1):2127.
Hoersch D, Roh SH, Chiu W, Kortemme T. (2013) Reprogramming an ATP-driven protein machine into a light-gated nanocage. Nat Nanotechnol. 8(12):928-32.
Eames M, Kortemme, T. (2012). Cost-benefit tradeoffs in engineered lac operons. Science 336(6083): 911-915.
Kapp GT, Liu S, Stein A, Wong DT, Reményi A, Yeh BJ, Fraser JS, Taunton J, Lim WA, Kortemme T. (2012). Control of protein signaling using a computationally designed GTPase/GEF orthogonal pair. Proc Natl Acad Sci U S A. 109(14): 5277-82.
Mandell DJ, Coutsias EA, Kortemme T. (2009). Sub-angstrom accuracy in protein loop reconstruction by robotics-inspired conformational sampling. Nat Methods 6:551–552.
Smith CA, Kortemme T. (2008). Backrub-like backbone simulation recapitulates natural protein conformational variability and improves mutant side-chain prediction. J Mol Biol. 380(4):742-56.
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Highlights from the Lab
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Tina and Chris's work on Gsp1 was selected for a "Spotlight" piece in Trends in Biochemical Sciences.
A kinetic mechanism for systems-level behavior in GTPase signaling |
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UCSF has written up a nice highlight on Tina and Chris's paper in Nature describing the cellular effects of allosteric mutations in Gsp1
How Cells Multitask: The Magic of Molecular Switches |
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Samuel's QBI interview for the 2017 Dr. Herbert Landahl Mathematical Biophysics Student Excellence Award.
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Our biosensor project wins first prize in Gen9's inaugural G-Prize contest
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