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David A. Tirrell

February 12, 2007 | A version of this story appeared in Volume 85, Issue 7

Credit: Courtesy of David Tirrell
Credit: Courtesy of David Tirrell

Linda Raber

Over the past 26 years, David A. Tirrell, Ross McCollum-William H. Corcoran Professor and professor of chemistry and chemical engineering at California Institute of Technology, has made major contributions to polymer and materials chemistry. His primary areas of research have been chemical modification of polymers, radical copolymerization mechanisms, drug delivery systems, development of molecular biological approaches to new materials, and fabrication of nanometer-scale conduits, networks, and wires. In each area, novel conception and careful execution have characterized the work.

By using artificial genes to direct the synthesis of long-chain artificial proteins, Tirrell created a new class of macromolecular materials that combine structure and function in unique ways.

His earliest experiments addressed structural issues. Synthetic polymers of sufficiently regular molecular architecture can organize in the solid state into lamellar crystals in which the chains are forced to fold at the lamellar surfaces. But such lamellae are metastable, and their organization is not related in any simple way to the molecular structure of the constituent chains.

Tirrell sought to control the chain-folded architecture through the design and microbial expression of periodic polypeptide sequences in which the sequence periodicity would determine the thickness and surface chemistry of the lamellar crystals. This idea provided a powerful new method of controlling macromolecular crystallization and has been expanded to the control of unit-cell parameters and of β-sheet symmetry.

One of the most intriguing prospects Tirrell's research has raised is the possibility that genetic information can be used to dictate structural organization in polymeric systems at length scales significantly greater than those characteristic of the isolated macromolecule. In recent experiments, he has shown, for example, that chain-length control can be exploited to engineer—at the angstrom level—the interlayer spacing in smectic liquid-crystal phases of rodlike polymers.

Tirrell's work on artificial protein design has opened fundamentally new approaches to the preparation of macromolecular materials that combine the materials behavior of conventional polymers with the functional properties of natural proteins. A recent paper describes the synthesis of multidomain artificial proteins in which leucine-zipper endblocks flank a central hydrophilic polyelectrolyte domain. Because dimerization and higher-order aggregation of the leucine-zipper domains is sensitive to pH and temperature, these multidomain polymers exhibit viscoelastic properties that are easily controlled.

One of most striking results of Tirrell's research has been the demonstration of the extent to which proteins can be constructed from nonnatural amino acids. By clever choice of side-chain geometry and functionality, he has identified several dozen new monomers that function as amino acid "surrogates" in that they can replace the natural amino acids normally used by cells to build proteins. These experiments have shown the introduction of alkenes, alkynes, thiophenes, fluorides, nitriles, azides, cyclobutenes, ketones, and bromides into artificial proteins made in bacterial cells.

Incorporation of noncanonical amino acids into recombinant proteins is not straightforward, because one must find efficient means of attaching the novel substrate to the appropriate transfer RNA in vivo. Tirrell's group has attacked this problem by preparing bacterial strains characterized by altered aminoacyl-tRNA synthetase activities. The group achieved this either by increasing the activity of the wild-type synthetases or by preparing mutant synthetases with expanded synthetic sites or occluded editing sites.

In continued progress, his group has developed macromolecular fibrils and scaffolds for protein immobilization. Colleagues anticipate that his manipulation of codon reassignment will catalyze many new developments in peptide design and synthesis.

Tirrell, 54, received a B.S. degree in chemistry from Massachusetts Institute of Technology and M.S. and Ph.D. degrees in polymer science and engineering from the University of Massachusetts, Amherst. Before joining Caltech in 1998, he held faculty positions at Carnegie Mellon University and the University of Massachusetts. Among his many awards are the Carl S. Marvel Creative Polymer Chemistry Award and the 2001 ACS Award in Polymer Chemistry.


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