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TITLE:
Modelling Electrostatic Effects in Protein Structure and Function
SPEAKER:
Dr. Donald Bashford,
TIME: Thursday Dec. 2, 2004 at 4 PM
PLACE: George P. Williams, Jr. Lecture Hall, (Olin 101)
Hartwell Center for Bioinformatics and
Biotechnology
St. Jude Children's Research Hospital
Memphis, TN
Electrostatic effects present a special challenge for simulation and
modelling in proteins because proteins contain many charged or polar
groups, and water is a highly polar solvent. While explicit solvent
simulations are the most rigorous practical method, it is costly and
subject to convergence problems. Continuum models offer lower
computational cost and well converged energetics within a limited
model, but that model may neglect important conformational effects.
Protonation states and pKa values of sidechains in proteins offer an
almost ideal test of electrostatic methods and are often of great
interest in understanding protein function. Bacteriorhodopsin, a
light-driven trans-membrane proton pump, has a number of sidechains
with very unusual ionization states which continuum theory can predict
correctly, and highly shifted pKa values for which continuum theory
gives reasonable estimates. To understand pumping, we must move beyond
equilibrium concepts of pKa and consider sequences of
protonation-state changes and conformational changes that are
energetically coupled. We present a transition rule-based approach
and a full kinetic model based on a master-equation approach.
We have also investigated the energetics of the stabilization of the
tetramerization domain of p53, a tumor suppressor protein that is
often mutated in cancer. We compare explicit water and Generalized
Born methods of handling electrostatics in the simulations, and
present novel features that emerge in simulations revealing
stabilizing factors not apparent in the crystal structure.