Proteins are large, complex molecules that perform the critical biological functions of molecular recognition, catalysis, and transport and energy conversion. They can do this because they are able to adopt stable three-dimensional structures that hold functional groups in precise orientations consistent with their function. They are like tiny assembly-line robots that recognize specific molecules and alter them according to their DNA-programmed function. Proteins are very difficult to design because they adopt their three-dimensional structures through a very complex process called protein-folding. If we are to develop the ability to rapidly create large molecules that can carry out complex functions like proteins do, we need to develop new ways of synthesizing large molecules with programmable shapes.
Over the past seven years, my laboratory has developed a radical new approach to creating large, complex molecules that can carry out complex functions in the way that biological proteins do. Our approach is to synthesize new stereochemically pure cyclic bis-amino acid building blocks (Molecular Lego) that we couple through pairs of amide bonds to create large molecules with programmed shapes. The oligomers are efficiently assembled on solid support using peptide synthesis techniques to first create a flexible oligomer that is then rigidified by the simultaneous formation of a second set of amide bonds between each adjacent pair of monomers. The structure of the resulting ladder-like molecules is controlled by the sequence and stereochemistry of the component monomers. The oligomer structures made accessible by this technology range from extended molecular rods to compact structures containing small-molecule sized cavities. These oligomers can be functionalized in a variety of ways to carry out different functions.
We are developing a software package that will enable anyone to construct oligomer sequences with designed shapes, either interactively or through automated computer searches of sequence space. Our goal is to combine this software and molecular “hardware” to create a sort of “molecular compiler” that can take a high level specification of a function (eg: catalyze a particular reaction) and convert it into a molecular implementation that will carry out that function.
Chris Schafmeister recently joined Temple University as an Associate Professor in Chemistry. Prior to that he was an Assistant Professor at the University of Pittsburgh and a Postdoctoral Fellow at Harvard. He received his PhD in Biophysics from UCSF. Among other awards, Chris received the Feynman Prize for Experimental Nenotechnology in 2005. His current research focus is on developing applications for functional macromolecules constructed from asymmetric molecular building blocks.