Designer Generation: Chemical and Computational Tools for Biological Problems

Designer Generation
Reported by
Sarah Webb

Posted September 11, 2007


Chemical biology encompasses a wide variety of chemical techniques aimed at achieving a better understanding of, and perhaps optimizing, biological systems. The year-end meeting of the Chemical Biology Discussion Group, held on June 5, 2007 at the New York Academy of Sciences, opened with a keynote talk from one of the leaders in the field of computational protein design.

With computational design as a centerpiece, the second half of the program showcased the breadth of the field, focusing on mechanistic studies and drug discovery, novel biomimetic scaffolds, hybrid chemical strategies for producing biologically relevant materials, and directed evolution. These half-dozen talks highlighted work from local up-and-coming researchers: students and postdoctoral associates at institutions in the greater New York City area. The format has become a tradition of the year-end meeting, noted organizer Virginia Cornish of Columbia University, and the session was packed to capacity with both faculty members and science trainees.

Journal Articles

Computational Design of Protein Function: Theory, Experiments, Applications

Allert M, Dwyer MA, Hellinga HW. 2006. Local encoding of computationally designed enzyme activity. J. Mol. Biol. 366: 945-953.

Allert M, Rizk SS, Looger LL, Hellinga HW. 2004. Computational design of receptors for an organophosphate surrogate of the nerve agent soman. Proc. Natl. Acad. Sci. USA 101: 7907-7912. Full Text

Cox C, Lape J, Sayed MA, Hellinga HW. 2007. Protein fabrication automation. Prot. Sci. 16: 379-390.

Dattelbaum JD, Looger LL, Benson DE, et al. 2005. Analysis of allosteric signal transduction mechanisms in an engineered fluorescent maltose biosensor. Prot. Sci. 14: 284-291. Full Text

De Lorimier RM, Tian Y, Hellinga HW. 2006. Binding and signaling of surface-immobilized reagentless fluorescent biosensors derived from periplasmic binding proteins. Prot. Sci. 15: 1936-1944. Full Text

De Lorimier RM, Smith JJ, Dwyer MA, et al. 2002. Construction of a fluorescent biosensor family. Prot. Sci. 11: 2655-2675. Full Text

Dwyer MA, Looger LL, Hellinga HW. 2004. Computational design of a biologically active enzyme. Science 304: 1967-1971.

Griffin BA, Adams SR, Tsien RY. 1998. Specific covalent labeling of recombinant protein molecules inside live cells. Science 281: 269-272.

Hellinga HW, Marvin JS. 1998. Protein engineering and the development of generic biosensors. Trends Biotech. 16: 183-189.

Liu H, Schmidt JJ, Bachand GD, et al. 2002. Control of a biomolecular motor-powered nanodevice with an engineered chemical switch. Nature Materials 1: 173-177.

Looger LL, Dwyer MA, Smith JJ, Hellinga HW. 2003. Computational design of receptor and sensor proteins with novel functions. Nature 423: 185-190.

Looger LL, Hellinga HW. 2001. Generalized dead-end elimination algorithms make large-scale protein side-chain structure prediction tractable: implications for protein design and structural genomics. J. Mol. Bio. 307: 429-445.

Marvin JS, Corcoran EE, Hattangadi NA, et al. 1997. The rational design of allosteric interactions in a monomeric protein and its applications to the construction of biosensors. Proc. Natl. Acad. Sci. USA 94: 4366-4371. Full Text

Marvin JS, Hellinga HW. 2001. Manipulation of ligand binding affinity by exploitation of conformational coupling. Nature Struct. Biol. 8: 795-798.

Rizk SS, Cuneo MJ, Hellinga HW. 2006. Identification of cognate ligands for the Escherichia coli phnD protein product and engineering of a reagentless fluorescent biosensor for phosphonates. Prot. Sci. 15: 1745-1751. Full Text

Wisz MS, Hellinga HW. 2003. An empirical model for electrostatic interactions in proteins incorporating multiple geometry-dependent dielectric constants. Proteins 51: 360-377.

Picomolar Inhibitors as Transition State Probes of 5′-Methylthioadenosine Nucleosidases (MTAN)

Singh V, Shi W, Almo SC, et al. 2006. Structure and inhibition of a quorum sensing target from Streptococcus pneumoniae. Biochemistry 45: 12929-12941.

Taylor Ringia EA, Tyler PC, Evans GB, et al. 2006. Transition state analogue discrimination by related purine nucleoside phosphorylases. J. Am. Chem. Soc. 128: 7126-7127.

KasA Inhibition by Thiolactomycin: Mechanism and Lead Optimization Studies

Price AC, Choi K-H, Heath RJ, et al. 2001. Inhibition of β-ketoacyl-acyl carrier protein synthases by thiolactomycin and cerulenin. Structure and mechanism. J. Biol. Chem. 276: 6551-6559. Full Text

Xu Y, Heath RJ, Li Z, et al. 2001. The FadR-DNA complex. Transcriptional control of fatty acid metabolism in Escherichia coli. J. Biol. Chem. 276: 17373-17379. Full Text

Zhang Y-M, Rao MS, Heath RJ, et al. 2001. Identification and analysis of the acyl carrier protein (ACP) docking site on beta-ketoacyl-ACP synthase III. J. Biol. Chem. 276: 8231-8238. Full Text

Cyclic Peptidomimetics

Angell Y, Burgess K. 2005. Ring closure to beta-turn mimics via copper-catalyzed azide/alkyne cycloadditions. J. Org. Chem. 70: 9595-9598.

Fujimura F, Kimura S. 2007. Columnar assembly formation and metal binding of cyclic tri-beta-peptides having terpyridine ligands. Org. Lett. 9: 793-796.

Garanger E, Boturyn D, Coll J.-L, et al. 2006. Multivalent RGD synthetic peptides as potent alphaVbeta3 integrin ligands. Org. Biomol. Chem. 4: 1958-1965.

Shin SBY, Yoo B, Todaro LJ, Kirshenbaum K. 2007. Cyclic peptoids. J. Am. Chem. Soc. 129: 3218-3225.

Computational Design and Experimental Characterization of an Electron Transfer Membrane Protein

Fang C, Senes A, Cristian L, et al. 2006. Amide vibrations are delocalized across the hydrophobic interface of a transmembrane helix dimer. Proc. Nat.l Acad. Sci. USA 103: 16740-16745. Full Text

Senes A, Chadi DC, Law PB, et al. 2007. E(z), a depth-dependent potential for assessing the energies of insertion of amino acid side-chains into membranes: derivation and applications to determining the orientation of transmembrane and interfacial helices. J. Mol Biol. 366: 436-448.

Senes A, Engel DE, DeGrado WF. 2004. Folding of helical membrane proteins: the role of polar, GxxxG-like and proline motifs. Curr. Opin. Struct. Biol. 14: 465-479.

Directed Evolution of Cellulases via Chemical Complementation

Baker K, Bleczinski C, Lin H, et al. 2002. Chemical complementation: A reaction-independent genetic assay for enzyme catalysis. Proc. Natl. Acad. Sci. USA 99: 16537-16542. Full Text

Lin H, Tao H, Cornish VW. 2004. Directed evolution of a glycosynthase via chemical complementation. J. Am. Chem. Soc. 126: 15051-15059.

Tao H, Peralta-Yahya P, Lin H, Cornish VW. 2006. Optimized design and synthesis of chemical dimerizer substrates for detection of glycosynthase activity via chemical complementation. Bioorg. Med. Chem. 14: 6940-6953.

Site-Specific H2B Ubiquitylation

Chatterjee C, McGinty RK, Pellois J-P, Muir TW. 2007. Auxiliary-mediated site-specific peptide ubiquitylation. Angew Chem. Int. Ed. 46: 2814-2818.

Hahn ME, Muir TW. 2005. Manipulating proteins with chemistry: a cross-section of chemical biology. Trends Biochem. Sci. 30: 26-34.

Muralidharan V, Muir TW. 2006. Protein ligation: an enabling technology for the biophysical analysis of proteins. Nat. Methods 3: 429-438.

Pellois JP, Muir TW. 2006. Semisynthetic proteins in mechanistic studies: using chemistry to go where nature can't. Curr. Opin. Chem. Biol. 10: 487-491.

Keynote Speaker

Homme W. Hellinga, PhD

Duke University
e-mail | web site | publications

Homme Hellinga received his undergraduate degree from the University of Edinburgh and his PhD degree from the University of Cambridge. He worked as a postdoctoral researcher in the R.L. Baldwin's lab at Stanford University and then joined the research faculty at Yale University in 1987. In 1992, he moved to Duke University, where he is now the James B. Duke Professor of Biochemistry. A recipient of the 2003 Kaiser Award from the Protein Society, Hellinga is recognized as a leader in the field of synthetic biology. He was among the first group of NIH Pioneer Award recipients in 2004.


Minkui Luo, PhD

Albert Einstein College of Medicine
e-mail | web site | publications

Minkui Luo received his undergraduate degree in 1999 from Fudan University in Shanghai, China and completed his PhD degree in 2005 at Princeton University in the laboratory of John T. Groves. Since then, he has been working as a postdoctoral researcher in the laboratory of Vern L. Schramm at Albert Einstein College of Medicine in the Bronx.

Carl Machutta

Stony Brook University
e-mail | web site | publications

After completing his undergraduate degree in biochemistry in 2002, Carl Machutta remained at Stony Brook University for PhD work in the laboratory of Peter Tonge.

Barney Yoo

New York University
e-mail | web site | publications

Barney Yoo is a PhD student in Kent Kirshenbaum's laboratory at New York University.

Alessandro Senes, PhD

University of Pennsylvania
e-mail | web site | publications

Alessandro Senes received his undergraduate degree in biology from the University of Sassari, Italy and completed his PhD in Molecular Biophysics and Biochemistry working in Don Engelman's laboratory at Yale University. He is currently a postdoctoral research associate at the University of Pennsylvania in the laboratory of William F. DeGrado.

Pamela Peralta-Yahya

Columbia University
e-mail | web site | publications

Pamela Peralta-Yahya completed her undergraduate degree in chemistry and biology at Macalester College in Saint Paul, Minnesota. She is a PhD candidate in Virginia Cornish's laboratory at Columbia University.

Robert McGinty

The Rockefeller University
e-mail | web site | publications

Robert McGinty received his undergraduate degree at Iowa State University in 2003. He is currently pursuing thesis research in Tom Muir's laboratory at the Rockefeller University as part of his studies in the Tri-Institutional MD-PhD program.

Sarah Webb

Before hanging up her labcoat, Sarah Webb earned a PhD in bioorganic chemistry. Based in Brooklyn, NY, she writes about science, health, and technology for publications including Science, Science News, Discover and Science News for Kids.