Past Event: Oden Institute Seminar

Protein Electrostatics: Experimental insights that challenge the paradigm

Bertrand Garcia-Moreno, Johns Hopkins University

Abstract

Correlation between the structure and the function of proteins requires deep, detailed understanding of the magnitude and determinants of electrostatic effects. Today this is approached mostly through structure-based calculations of electrostatic fields and energies. Unfortunately, despite their widespread use, these calculations are not accurate and they are rarely useful. They remain a daunting challenge for reasons I will discuss using data from equilibrium thermodynamic, x-ray crystallography and NMR spectroscopy experiments designed to measure the magnitude and character of electrostatic effects of surface residues. I will also discuss results from on-going structural and thermodynamic studies of the highly anomalous properties of ionizable groups buried in dry or hydrophobic environments in proteins. These studies are contributing truly novel insight into determinants of electrostatic effects and they are revealing why accurate and useful structure-based calculations remain so challenging. I will end by discussing our efforts to harness the unusual properties of buried groups to engineer protein pH sensors and switches that respond dramatically to small changes in pH. These efforts touch on the roles of proteins as biological pH sensors and switches in cancer and in other disease states where pH homeostasis is dysregulated.