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How to Build a Better Protein: Advances in Biomolecular Engineering

How to Build a Better Protein
Reported by
Megan Stephan

Posted September 14, 2007


Chemical engineers have long envied the elegant way that biological enzymes perform their tasks. These molecules, usually proteins, catalyze complex chemical reactions under mild temperature, pressure, and pH conditions. They work in aqueous solution, without the need for organic solvents. And perhaps most attractively, they can be exquisitely selective in their choice of substrates and the specificity of their products.

Protein engineers are looking to pick up where evolution left off and design proteins that can make plastic-like polymers and carry out other desirable reactions under mild conditions. They are also working to improve or change the functions of proteins with potential medical or bioengineering uses, such as monoclonal antibodies or the structural protein collagen. On May 22, 2007, seven such engineers presented their work to others in their field at a conference titled Advances in Biomolecular Engineering: Protein Design Symposium, held at the Polytechnic University in Brooklyn, NY.

Web Sites

Biocatalysis/Biodegradation Database
University of Minnesota resource for information on microbial biocatalytic reactions and biodegradation pathways.

Comprehensive collection of enzyme functional data maintained at the Cologne University Bioinformatics Center.

EPA Green Chemistry Program
Promoting innovative chemical technologies that reduce or eliminate the use or generation of hazardous substances in the design, manufacture, and use of chemical products.

Mike's Immunoglobulin Structure/Function Home Page
Webpages on immunoglobulin structure and function prepared by Mike Clark, PhD, Cambridge University, Cambridge UK.

Protein Information Resource
Centralized resource for protein sequences, functional information and analytical tools.

The Protein Society
The leading international society devoted to furthering research and development in protein science.

Society for Biomaterials
Promotes the discipline of biomaterials and their uses in medical and surgical devices including synthetic, natural, and biologically sourced materials.

Journal Articles

Novel Proteomes from Designed Combinatorial Libraries

Bradley LH, Kleiner RE, Wang AF, et al. 2005. An intein-based genetic selection allows the construction of a high-quality library of binary patterned de novo protein sequences. Protein Eng. Des. Sel. 18: 201-207.

Bradley LH, Thumfort PP, Hecht MH. 2006. De novo proteins from binary-patterned combinatorial libraries. Methods Mol. Biol. 340: 53-69.

Bradley LH, Wei Y, Thumfort P, et al. 2007. Protein design by binary patterning of polar and nonpolar amino acids. Methods Mol. Biol. 352: 155-66.

Das A, Trammell SA, Hecht MH. 2006. Electrochemical and ligand binding studies of a de novo heme protein. Biophys. Chem. 123: 102-112.

Hecht MH, Das A, Go A, et al. 2004. De novo proteins from designed combinatorial libraries. Protein Sci. 13: 1711-1723. Full Text

Wei Y, Liu T, Sazinsky SL, et al. 2003. Stably folded de novo proteins from a designed combinatorial library. Protein Sci. 12: 92-102. Full Text

Wei Y, Kim S, Fela D, et al. 2003. Solution structure of a de novo protein from a designed combinatorial library. Proc. Natl Acad. Sci. USA 100: 13270-13273. Full Text

Wei Y, Hecht MH. 2004. Enzyme-like proteins from an unselected library of designed amino acid sequences. Protein En. Des. Sel. 17: 67-75. Full Text

Chemical Complementation: Engineering the Cell for Directed Evolution

de Felipe KS, Carter BT, Althoff EA, et al. 2004. Correlation between ligand-receptor affinity and the transcription readout in a yeast three-hybrid system. Biochemistry 43: 10353-10363.

Gallagher SS, Miller LW, Cornish VW. 2007. An orthogonal dexamethasone-trimethoprim yeast three-hybrid system. Anal. Biochem. 363: 160-162.

Lefurgy S, Cornish V. 2004. Finding Cinderella after the ball: a three-hybrid approach to drug target identification. Chem. Biol. 11:151-153.

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

Sengupta D, Lin H, Goldberg SD, et al. 2004. Correlation between catalytic efficiency and the transcription read-out in chemical complementation: a general assay for enzyme catalysis. Biochemistry 43: 3570-3581.

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

Engineering Collagen: Nature's Rope

Hodges JA, Raines RT. 2006. Energetics of an n → pi interaction that impacts protein structure. Org. Lett. 8: 4695-4697.

Hodges JA, Raines RT. 2005. Stereoelectronic and steric effects in the collagen triple helix: toward a code for strand association. J. Am. Chem. Soc. 127: 15923-15932.

Horng JC, Hawk AJ, Zhao Q, et al. 2006. Macrocyclic scaffold for the collagen triple helix. Org. Lett. 8: 4735-4738.

Horng JC, Raines RT. 2006. Stereoelectronic effects on polyproline conformation. Protein Sci. 15: 74-83.

Kotch FW, Raines RT. 2006. Self-assembly of synthetic collagen triple helices. Proc. Natl. Acad. Sci. USA 103: 3028-3033. Full Text

Shoulders MD, Hodges JA, Raines RT. 2006. Reciprocity of steric and stereoelectronic effects in the collagen triple helix. J. Am. Chem. Soc. 128: 8112-8113.

Microbe and Enzyme Engineering to Prepare Poly(ω-hydroxy fatty acid)s from Fatty Acids via P450 and Lipase-catalyzed Reactions

Azim H, Dekhterman A, Jiang Z, et al. 2006. Candida antarctica lipase B-catalyzed synthesis of poly(butylene succinate): shorter chain building blocks also work. Biomacromolecules 7: 3093-3097.

Chen B, Miller ME, Gross RA. 2007. Effects of porous polystyrene resin parameters on Candida antarctica lipase B adsorption, distribution, and polyester synthesis activity. Langmuir 23: 6467-6474.

Chen B, Miller EM, Miller L, et al. 2007. Effects of macroporous resin size on Candida antarctica lipase B adsorption, fraction of active molecules, and catalytic activity for polyester synthesis. Langmuir 23: 1381-1387.

Gross RA, Kalra B. 2002. Biodegradable polymers for the environment. Science 297: 803-807.

Mahapatro A, Kumar A, Gross RA. 2004. Mild, solvent-free omega-hydroxy acid polycondensations catalyzed by candida antarctica lipase B. Biomacromolecules 5: 62-68.

Protein Engineering in Biomedicine

Chao G, Lau WL, Hackel BJ, et al. 2006. Isolating and engineering human antibodies using yeast surface display. Nat. Protoc. 1: 755-768.

Lipovsek D, Lippow SM, Hackel BJ, et al. 2007. Evolution of an interloop disulfide bond in high-affinity antibody mimics based on fibronectin type III domain and selected by yeast surface display: molecular convergence with single-domain camelid and shark antibodies. J. Mol. Biol. 368: 1024-1041.

Peelle BR, Krauland EM, Wittrup KD, et al. 2005. Probing the interface between biomolecules and inorganic materials using yeast surface display and genetic engineering. Acta Biomater. 1: 145-154.

Piatesi A, Howland SW, Rakestraw JA, et al. 2006. Directed evolution for improved secretion of cancer-testis antigen NY-ESO-1 from yeast. Protein Expr. Purif. 48: 232-242.

Rakestraw JA, Baskaran AR, Wittrup KD. 2006. A flow cytometric assay for screening improved heterologous protein secretion in yeast. Biotechnol. Prog. 22: 1200-1208.

Thurber GM, Zajic SC, Wittrup KD. 2007. Theoretic criteria for antibody penetration into solid tumors and micrometastases. J. Nucl. Med. 48: 995-999.

Use of Proteomics in the Development of Ghost Vaccines

Alefantis T, Grewal P, Ashton J, et al. 2004. A rapid and sensitive magnetic bead-based immunoassay for the detection of staphylococcal enterotoxin B for high-through put screening. Mol. Cell Probes. 18: 379-382.

Brumlik MJ, Szymajda U, Zakowska D, et al. 2001. Use of long-range repetitive element polymorphism-PCR to differentiate Bacillus anthracis strains. Appl. Environ. Microbiol. 67: 3021-3028. Full Text

Redkar RJ, Dube MP, McCleskey FK, et al. 1996. DNA fingerprinting of Candida rugosa via repetitive sequence-based PCR. J. Clin. Microbiol. 34: 1677-1681. Full Text

Del Vecchio VG, Petroziello JM, Gress MJ, et al. 1995. Molecular genotyping of methicillin-resistant Staphylococcus aureus via fluorophore-enhanced repetitive-sequence PCR. J. Clin. Microbiol. 33: 2141-2144. Full Text

Protein Design at the Crossroads: Using Computation to Accelerate Discovery

Allen BD, Mayo SL. 2006. Dramatic performance enhancements for the FASTER optimization algorithm. J. Comput. Chem. 27: 1071-1075.

Alvizo O, Allen BD, Mayo SL. 2007. Computational protein design promises to revolutionize protein engineering. Biotechniques 42: 31, 33, 35 passim.

Mena MA, Treynor TP, Mayo SL & Daugherty PS. 2006. Blue fluorescent proteins with enhanced brightness and photostability from a structurally targeted library. Nat. Biotechnol. 24: 1569-1571.

Treynor TP, Vizcarra CL, Nedelcu D & Mayo SL. 2007. Computationally designed libraries of fluorescent proteins evaluated by preservation and diversity of function. Proc. Natl. Acad. Sci. USA 104: 48-53. Full Text

Vizcarra CL, Mayo SL. 2005. 2005. Electrostatics in computational protein design. Curr. Opin. Chem. Biol. 9: 622-626.

Zollars ES, Marshall SA, Mayo SL. 2006. Simple electrostatic model improves designed protein sequences. Protein Sci. 15: 2014-2018. Full Text


Michael H. Hecht, PhD

Princeton University
e-mail | web site | publications

Michael Hecht is a professor in the Department of Chemistry at Princeton University. He is currently director of Undergraduate Studies and associate department chair. Hecht received his PhD from MIT in the lab of Bob Sauer. After receiving his PhD, he did postdoctoral work at Duke University with David and Jane Richardson. In 1990, he moved to Princeton University as an assistant professor. His awards include the Protein Society's Kaiser Award, and the Beckman Young Investigator Award. He was also awarded the Whitaker Foundation Young Investigator Fellowship and was a National Science Foundation Graduate Fellow.

Hecht is on the editorial advisory board of the journals Protein Science and Protein Engineering, Design & Selection. His research interests include protein folding and stability, de novo protein design, combinatorial methods for constructing protein libraries, protein misfolding, and the role of amyloid in Alzheimer's disease.

Virginia W. Cornish, PhD

Columbia University
e-mail | web site | publications

Virginia Cornish is a professor in the Department of Chemistry at Columbia University. She did her graduate work in the laboratory of Pete Schultz in the Chemistry Department at the University of California at Berkeley. In 1996, she became a National Science Foundation Postdoctoral Fellow in the Biology Department at MIT under the guidance of Bob Sauer.

Cornish joined the Columbia faculty in 1999. Her laboratory is using a combination of synthetic chemistry and molecular genetics to develop a cell-based assay for screening large collections of compounds simultaneously based on function. She is the recipient of a Beckman Young Investigator Award, a Burroughs-Wellcome Fund New Investigator Award in the Toxological Sciences, a Camille and Henry Dreyfus New Faculty Award, and a National Science Foundation Career Award.

Ronald T. Raines, PhD

University of Wisconsin, Madison
e-mail | web site | publications

Ronald Raines is the Henry Lardy Professor of Biochemistry at the University of Wisconsin, Madison. He is also a member of the Department of Chemistry. Raines received his PhD from Harvard University. He has received numerous awards including the the Protein Society's Kaiser Award, The American Chemical Society's Arthur C. Cope Scholar Award and the Vilas Associates Award in the Biological Sciences Division from the University of Wisconsin, Madison. Raines has also received many fellowships including the Guggenheim Fellowship and an AAAS fellowship. His laboratory is interested in chemical biology, protein design and engineering, and enzymology.

Richard A. Gross, PhD

Polytechnic University
e-mail | web site | publications

Richard Gross is the Herman F. Mark Professor of Polymer Science in the Department of Chemical and Biological Sciences and director of the NSF Center for Biocatalysis and Bioprocessing of Macromolecules at Polytechnic University. Gross received a Presidental Green Chemistry Award in 2003.

Research in the Gross laboratory encompasses a wide variety of projects directed toward development of new enzyme and chemo-enzymatic strategies and methods for the synthesis of polymers for a wide variety of applications. Gross received his PhD in organic-polymer chemistry from the university in 1986.

K. Dane Wittrup, PhD

Massachusetts Institute of Technology
e-mail | web site | publications

Dane Wittrup is the Joseph R. Mares Professor of Chemical Engineering & Bioengineering at the Massachusetts Institute of Technology. Previous appointments have included J.W. Westwater Professor of Chemical Engineering, Biophysics, and Bioengineering at the University of Illinois at Urbana-Champaign. He was also a postdoctoral research associate of the Yeast Molecular Biology Group at Amgen, Inc.

Wittrup has been the recipient of numerous awards and honors including the Fellow of the American Institute of Biomedical Engineers, and the Allan P. Colburn Award from the American Institute of Chemical Engineering. His research interests include molecular bioengineering, protein engineering, and therapeutic protein biotechnology.

Wittrup received his PhD from the California Institute of Technology in 1988.

Vito G. DelVecchio, PhD

Vital Probes Inc.
e-mail | publications

Vito DelVecchio is the founder and chief executive officer of Vital Probes, Inc. DelVecchio earned an MS in genetics from Saint John's University and a PhD in biochemical genetics from Hahneman Medical College. He conducted postdoctoral research at the University of Geneva. At the Carnegie-Mellon Research Institute in Pittsburgh he was project director of Fungal Genetics. DelVecchio was also a resident researcher at the Department of Epidemiology and Bacteriology at Brooks Air Force Base in San Antonio. Before founding Vital Probes, Inc. in 2000, he established the Institute of Molecular Biology and Medicine at the University of Scranton.

DelVecchio's research involves the study, rapid diagnosis, and detection of a wide range of microorganisms, especially those that can be used as biological warfare agents. In 2001 he organized and headed an international team of scientists which completely sequenced and annotated the genome of Brucella melitensis, a highly virulent biological warfare agent and pathogen to humans and commercial livestock.

Stephen Mayo, PhD

California Institute of Technology
e-mail | web site | publications

Steve Mayo is a professor of biology and chemistry at the California Institute of Technology and an investigator in the Structural Biology section at the Howard Hughes Medical Institute. He received a BS degree in chemistry from the Pennsylvania State University, where he developed an interactive macromolecular modeling program with Roy Olofson and a PhD degree in chemistry from the California Institute of Technology, where he studied biological electron transfer with Harry Gray. Mayo developed a rule based molecular mechanics force field as a Miller Fellow at the University of California, Berkeley and studied hydrogen/deuterium exchange reactions in proteins as a postdoctoral fellow with Robert Baldwin at Stanford University School of Medicine.

In addition to cofounding Molecular Simulations, Inc. (currently Accelrys), Mayo cofounded Xencor in 1997 and serves on its scientific advisory board. In 2004 Mayo was elected to the National Academy of Sciences for his pioneering contributions in the field of protein design.

Megan Stephan

Megan Stephan studied transporters and ion channels at Yale University for nearly two decades before giving up the pipettor for the pen. She specializes in covering research at the interface between biology, chemistry and physics. Her work has appeared in The Scientist and Yale Medicine. Stephan holds a PhD in biology from Boston University.