P. Andrew Karplus

Proteins play central roles in all aspects of biochemistry. In addition to the proteins that serve as enzymes catalyzing the reactions of metabolism, there are, among others, structural proteins, protein hormones, transport proteins, cell surface receptors and proteins involved in the regulation of DNA replication and transcription.

A theme common to all classes of proteins is specific recognition and function through unique structure. To develop a better understanding of the mechanisms involved in the specificity of recognition and catalysis, we need detailed structural information. I am interested in using X-ray crystallography, complemented by protein chemistry, enzymology and theoretical approaches such as molecular dynamics, to obtain this detailed structural information. 

The protein structures we are working on are a diverse group. Proteins are chosen with the dual goal that their detailed study will lead to insights relevant for understanding the particular protein and to insights relevant to understanding general principles of protein structure, stability and function. Most project being worked on are collaborative and current projects include the following: studies of flavoenzymes to investigate how the enzyme:flavin interactions influence the electronic structure of the flavin, and modulate its reactivity (e.g., ferredoxin reductase and glutathione reductase); studies to investigate the structural, functional and evolutionary relationships among peroxiredoxins and to probe their role in hydrogen peroxide signaling in eukaryotes; studies on the fungal toxin "ToxA" from Pyrenophora tritici-repentis, the causitive agent of tan spot of wheat. This protein is the first protein known to get into a mature plant cell without aid of any apparatus coming from the organism that syntheisizes it. Our studies are aimed at deciphering how it gets into plant cells and how it kills those cells.

In addition to these studies we have lauched an effort to use empirical studies of ultrahigh-resolution protein structures in the protein data bank to characterize how protein covalent geometry varies with conformation.  The variation is substantial and has not been taken into account in crystallographic refinement protocols, nor in the most successful appications for homolgy modeling. Using the information we are gathering in these modeling applications should improve the accuracy of the resulting structures.