RESEARCH INTERESTS:Computational Protein Design / Protein-Protein Interactions / Structural Biology
We use a combination of computational and experimental methods to characterize and design proteins.
What is protein design? Most ambitiously it is the creation of novel proteins to perform useful tasks. At a more modest level it might be identifying amino acid mutations that enhance protein stability, alter binding specificity, or increase solubility.
How do we design proteins? We have developed a computer program that identifies low energy sequences for target structures or interfaces. In essence it is like solving a jigsaw puzzle. The pieces, in this case amino acids, must fit together so that there are no overlaps and little empty space. In addition, specific interactions like hydrogen bonding must be satisfied.
What are we currently designing? Our main focus is the design of protein-protein interfaces. We are developing methods for enhancing the affinity of existing interactions as well as creating new interactions from scratch. Potential uses for this technology include the creation of biosensors, probes to study cell biology, and therapeutics with enhanced activity.
To learn more about our research, please see our group web page. RECENT PUBLICATIONS:Renfrew PD, Butterfoss GL, Kuhlman B. Using quantum mechanics to improve estimates of amino acid side chain rotamer energies. Proteins. 2008 Jun;71(4):1637-46.
Hu X, Wang H, Ke H, Kuhlman B. High-resolution design of a protein loop. Proc Natl Acad Sci U S A. 2007 Nov 6;104(45):17668-73. 30.
Kapustina M, Weinreb V, Li L, Kuhlman B, Carter CW Jr. A conformational transition state accompanies tryptophan activation by B. stearothermophilus tryptophanyl-tRNA synthetase. Structure. 2007 Oct;15(10):1272-84.
Sammond DW, Eletr ZM, Purbeck C, Kimple RJ, Siderovski DP, Kuhlman B. Structure-based protocol for identifying mutations that enhance protein-protein binding affinities. J Mol Biol. 2007 Aug 31;371(5):1392-404.
Eletr ZM, Kuhlman B. Sequence determinants of E2-E6AP binding affinity and specificity. J Mol Biol. 2007 Jun 1;369(2):419-28.
Pham Y, Li L, Kim A, Erdogan O, Weinreb V, Butterfoss GL, Kuhlman B, Carter CW Jr. A minimal TrpRS catalytic domain supports sense/antisense ancestry of class I and II aminoacyl-tRNA synthetases. Mol Cell. 2007 Mar 23;25(6):851-62.
Leaver-Fay A, Butterfoss GL, Snoeyink J, Kuhlman B. Maintaining solvent accessible surface area under rotamer substitution for protein design. J Comput Chem. 2007 Jun;28(8):1336-41.
Dantas G, Corrent C, Reichow SL, Havranek JJ, Eletr ZM, Isern NG, Kuhlman B, Varani G, Merritt EA, Baker D. High-resolution structural and thermodynamic analysis of extreme stabilization of human procarboxypeptidase by computational protein design. J Mol Biol. 2007 Mar 2;366(4):1209-21.
Johnston CA, Lobanova ES, Shavkunov AS, Low J, Ramer JK, Blaesius R, Fredericks Z, Willard FS, Kuhlman B, Arshavsky VY, Siderovski DP. Minimal determinants for binding activated G alpha from the structure of a G alpha(i1)-peptide dimer. Biochemistry. 2006 Sep 26;45(38):11390-400.
Dantas G, Watters AL, Lunde BM, Eletr ZM, Isern NG, Roseman T, Lipfert J, Doniach S, Tompa M, Kuhlman B, Stoddard BL, Varani G, Baker D. Mis-translation of a computationally designed protein yields an exceptionally stable homodimer: implications for protein engineering and evolution. J Mol Biol. 2006 Oct 6;362(5):1004-24.
Liu Y, Kuhlman B. RosettaDesign server for protein design. Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W235-8.
Butterfoss GL, Kuhlman B. Computer-based design of novel protein structures. Annu Rev Biophys Biomol Struct. 2006;35:49-65. Review.
Ambroggio XI, Kuhlman B. Design of protein conformational switches. Curr Opin Struct Biol. 2006 Aug;16(4):525-30. Review.
Ambroggio XI, Kuhlman B. Computational design of a single amino acid sequence that can switch between two distinct protein folds. J Am Chem Soc. 2006 Feb 1;128(4):1154-61.
Hu X, Kuhlman B. Protein design simulations suggest that side-chain conformational entropy is not a strong determinant of amino acid environmental preferences. Proteins. 2006 Mar 15;62(3):739-48.
Eletr ZM, Huang DT, Duda DM, Schulman BA, Kuhlman B. E2 conjugating enzymes must disengage from their E1 enzymes before E3-dependent ubiquitin and ubiquitin-like transfer. Nat Struct Mol Biol. 2005 Oct;12(10):933-4.
Leaver-Fay A, Kuhlman B, Snoeyink J. An adaptive dynamic programming algorithm for the side chain placement problem. Pac Symp Biocomput. 2005:16-27.
Jiang L, Kuhlman B, Kortemme T, Baker D. A "solvated rotamer" approach to modeling water-mediated hydrogen bonds at protein-protein interfaces. Proteins. 2005 Mar 1;58(4):893-904.
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Biochemistry and Biophysics - UNC School of Medicine
