Ph.D., Columbia University
Students in the Schwabacher group gain broad experience in organic chemistry. Projects usually begin with multi step synthesis, and continue by studying the resulting molecules using various chemical and biochemical techniques.
Our work aims to understand and replicate the dramatic capabilities of biological molecules. Recognition and selective binding of one molecule by another is a key behavior of biological molecules that leads to most of their interesting and useful properties. Most drugs are simply molecules that bind selectively to a specific molecular site. An enzyme’s ability to catalyze a reaction forming only one enantiomer of a product can be described as a selectivity for binding to the transition state leading to that product. An enzyme can select a single substrate from a heterogeneous solution containing multiple species of similar chemical reactivity, and transform it into a single product with a rate acceleration of 1012 or higher.
Molecules that bind are useful as pharmaceuticals and for separation, transport, analysis, nanoscale structural organization, and catalysis. Antibodies that can recognize and bind tightly to a single molecular species are extremely valuable. They are broadly used in medical diagnostic testing and for identification in research settings. For all these reasons, we consider the study of binding to be significant.
Biomolecules which carry out such binding and catalytic roles, as well as those of signal and energy transduction, and structural organization, have large molecular weights (>104) and very complex three dimensional structures. Their structures are determined by folding of linear sequences into three dimensional structures, and self-assembly of subunits, controlled by the same interactions that are responsible for their binding of small molecules.
Our projects have been designed to investigate the way multiple interactions cooperate to lead to high specificity binding. One scheme is shown below (F. Wang). Assembly in the presence of a metal ion forms a complex that selectively binds a guest molecule using a well-oriented combination of hydrophobic and polar interactions. Variation of the metal changes the shape of the receptor: Zn2+ and Cu2+ complexes exhibit opposite non-polar shape preference.
Combinatorial chemistry is being applied to the problem of preparing and evaluating variants of this receptor, in order to identify new species with interesting and useful properties. (See work by Y. Shen and C. W. Johnson cited below.)
Questions we address in our work include these:
- What affects the strength of intrinsic attractive forces?
- How can selectivity arise from the juxtaposition of many small interactions?
- What kinds of structures are most useful as armatures for building complex binding sites, and how can they most efficiently be prepared?
- How can we easily identify interesting structures from among a large library?