Brian Kuhlman

Research: Computational protein design and structural biology

Brian Kuhlman

Professor of Biochemistry and Biophysics
Co-Director, UNC Molecular and Cellular Biophysics Program
(PhD - State University of New York, Stony Brook)

120 Mason Farm Road, CB# 7260
3096 Genetic Medicine Building
Chapel Hill, NC 27599-7260

Kuhlman Lab Website


    • W.M.Keck Foundation Distinguished Young Scholar in Medical Research, 2005-2010
    • Searle Scholar, 2004-2007
    • Beckman Young Investigator, 2004-2007
    • AAAS Newcomb Cleveland Prize, 2004
    • Foresight Institute Feynman Prize in Nanotechnology, 2004
    • Alfred P. Sloan Fellow, 2004


        Summary: The focus of my laboratory is the development and application of methods for protein design. Proteins are the ultimate nanomachines and weKuhlman graphic aim to develop methods that can be used to create novel proteins that perform useful tasks. Central to most projects in the laboratory is the molecular modeling software Rosetta. My laboratory is part of a multi institutional team of developers that maintains and extends the capabilities of Rosetta. We have used Rosetta to stabilize proteins, enhance protein binding affinities, redesign protein signaling networks, design new protein structures, and design new protein-protein interactions. We are continually striving to improve the accuracy of Rosetta as well as apply it to new and important biological problems.

        Currently, my laboratory is focused on three projects: the design of protein-protein interactions, the design of proteins that can be turned on and off with the light, and the improvement of computational methods for performing protein simulations. Designed protein binders can serve as affinity reagents for the creation of new biosensors and can act as competitive inhibitors with therapeutic value. Light activatable proteins allow scientists to control the activity of proteins in living cells with spatial and temporal resolution. In collaboration with Klaus Hahn’s lab at UNC, we have created a photoactivable variant of the small GTPase Rac1 that allows biologists to use narrow beams of light to move cells around in living animals. Lastly, improvements to the core routines of Rosetta allow for more accurate design and prediction simulations by the thousands of laboratories that have licensed the Rosetta software.

        Core Techniques:

        • Rosetta molecular modeling program
        • Protein Stabilization
        • Protein Interface Design
        • Protein Binding Analysis

        To learn more about our research, please see our group web page.

        PUBLICATIONS pubmed.png (click for Full Publication List)

        • Lewis SM, Wu X, Pustilnik A, Sereno A, Huang F, Rick HL, Guntas G, Leaver-Fay A, Smith EM, Ho C, Hansen-Estruch C, Chamberlain AK, Truhlar SM, Conner EM, Atwell S, Kuhlman B, Demarest SJ. Generation of bispecific IgG antibodies by structure-based design of an orthogonal Fab interface. Nat Biotechnol. 2014 Feb;32(2):191-8. doi: 10.1038/nbt.2797. Epub 2014 Jan 26. PubMed PMID: 24463572.
        • Der BS, Kuhlman B. Cages from coils. Nat Biotechnol. 2013 Sep;31(9):809-10.
        • Kamadurai HB, Qiu Y, Deng A, Harrison JS, Macdonald C, Actis M, Rodrigues P, Miller DJ, Souphron J, Lewis SM, Kurinov I, Fujii N, Hammel M, Piper R, Kuhlman B, Schulman BA. Mechanism of ubiquitin ligation and lysine prioritization by a HECT E3. Elife. 2013;2:e00828.
        • Drew K, Renfrew PD, Craven TW, Butterfoss GL, Chou FC, Lyskov S, Bullock BN,Watkins A, Labonte JW, Pacella M, Kilambi KP, Leaver-Fay A, Kuhlman B, Gray JJ,Bradley P, Kirshenbaum K, Arora PS, Das R, Bonneau R. Adding diverse noncanonical backbones to rosetta: enabling peptidomimetic design. PLoS One. 2013 Jul 15;8(7):e67051. doi: 10.1371/journal.pone.0067051.
        • Lyskov S, Chou FC, Conchúir SÓ, Der BS, Drew K, Kuroda D, Xu J, Weitzner BD, Renfrew PD, Sripakdeevong P, Borgo B, Havranek JJ, Kuhlman B, Kortemme T, Bonneau R, Gray JJ, Das R. Serverification of molecular modeling applications: the Rosetta Online Server that Includes Everyone (ROSIE). PLoS One. 2013 May 22;8(5):e63906. doi: 10.1371/journal.pone.0063906.
        • Der BS, Kluwe C, Miklos AE, Jacak R, Lyskov S, Gray JJ, Georgiou G, Ellington AD, Kuhlman B. Alternative computational protocols for supercharging protein surfaces for reversible unfolding and retention of stability. PLoS One. 2013 May 31;8(5):e64363.
        • Der BS, Kuhlman B. Strategies to control the binding mode of de novo designed protein interactions. Curr Opin Struct Biol. 2013 May 31 [Epub ahead of print]
        • Leaver-Fay A, O'Meara MJ, Tyka M, Jacak R, Song Y, Kellogg EH, Thompson J, Davis IW, Pache RA, Lyskov S, Gray JJ, Kortemme T, Richardson JS, Havranek JJ, Snoeyink J, Baker D, Kuhlman B. Scientific benchmarks for guiding macromolecular energy function improvement. Methods Enzymol. 2013;523:109-43.
        • Choi EJ, Jacak R, Kuhlman B. A structural bioinformatics approach for identifying proteins predisposed to bind linear epitopes on pre-selected target proteins. Protein Eng Des Sel. 2013 Apr;26(4):283-9.
        • Der BS, Jha RK, Lewis SM, Thompson PM, Guntas G, Kuhlman B. Combined computational design of a zinc-binding site and a protein-protein interaction: One open zinc coordination site was not a robust hotspot for de novo ubiquitin binding. Proteins. 2013 Mar 16.
        • Zhang J, Lewis SM, Kuhlman B, Lee AL. Supertertiary structure of the MAGUK core from PSD-95. Structure. 2013 Mar 5;21(3):402-13.
        • Brooks LM, Kuhlman BJ, McKesson DW, McCloskey L. Poor interoperability of the Adams-Harbertson method for analysis of anthocyanins: comparison with AOAC pH differential method. J AOAC Int. 2013 Jan-Feb;96(1):86-90.
        • Baker R, Lewis SM, Sasaki AT, Wilkerson EM, Locasale JW, Cantley LC, Kuhlman B, Dohlman HG, Campbell SL. Site-specific monoubiquitination activates Ras by impeding GTPase-activating protein function. Nat Struct Mol Biol. 2013 Jan;20(1):46-52
        • Stranges PB, Kuhlman B. A comparison of successful and failed protein interface designs highlights the challenges of designing buried hydrogen bonds. Protein Sci. 2013 Jan;22(1):74-82.
        • Murphy GS, Mills JL, Miley MJ, Machius M, Szyperski T, Kuhlman B. Increasing sequence diversity with flexible backbone protein design: the complete redesign of a protein hydrophobic core. Structure. 2012 Jun 6;20(6):1086-96.
        • Der BS, Edwards DR, Kuhlman B. Catalysis by a de novo zinc-mediated protein interface: implications for natural enzyme evolution and rational enzyme engineering. Biochemistry. 2012 May 8;51(18):3933-40.
        • Guntas G, Kuhlman B. Redesigning the NEDD8 pathway with a bacterial genetic screen for ubiquitin-like molecule transfer. J Mol Biol. 2012 May 4;418(3-4):161-6.
        • Stranges PB, Machius M, Miley MJ, Tripathy A, Kuhlman B. Computational design of a symmetric homodimer using β-strand assembly. Proc Natl Acad Sci U S A. 2011 Dec 20;108(51):20562-7.
        • Der BS, Machius M, Miley MJ, Mills JL, Szyperski T, Kuhlman B. Metal-mediated affinity and orientation specificity in a computationally designed protein homodimer. J Am Chem Soc. 2012 Jan 11;134(1):375-85.
        • Jha RK, Wu YI, Zawistowski J, Macnevin C, Hahn KM, Kuhlman B. Redesign of the  PAK1 Autoinhibitory Domain for Enhanced Stability and Affinity in Biosensor Applications. J Mol Biol. 2011 Aug 24
        • Sammond DW, Bosch DE, Butterfoss GL, Purbeck C, Machius M, Siderovski DP, Kuhlman B. Computational design of the sequence and structure of a protein-binding peptide. (2011) J Am Chem Soc. 133(12):4190-2.
        • Guntas G, Purbeck, C., Kuhlman, B. (2010) Engineering a Protein-Protein Interface using a Computationally Designed Library, Proc Natl Acad Sci, 107, 19296-301.
        • Kleiger G, Saha A, Lewis S, Kuhlman B, Deshaies RJ. (2009) Rapid E2-E3 assembly and disassembly enable processive ubiquitylation of cullin-RING ubiquitin ligase substrates. Cell 139, 957.
        • Wu, Y, Frey, D., Lungu, O. I., Jaehrig, A., Schlichting, I., Kuhlman, B. and Hahn, K.M. (2009) A genetically encoded photoactivatable Rac controls the motility of living cells. Nature, 461, 104-108.
        • Hu, X., Wang, H., Ke, H., & Kuhlman, B. (2007) High-resolution design of a protein loop. Proc Natl Acad Sci, 104, 17668-17673.
        • Kuhlman, B., Dantas, G., Ireton, G., Varani, G., Stoddard, B., & Baker, D. (2003) Design of a novel globular protein fold with atomic level accuracy.  Science 302, 1364-1368.

        Lab Contact:

        Lab Rooms: 3100D-F Genetic Medicine 
        Lab Phone: 919-966-6781
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