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Norma M. Allewell, Associate Fellow

Structure Determination and Modeling of Electrostatic Effects in Large Macromolecules

This project is using supercomputing resources for electrostatic modeling and crystallographic structure determination. A rapid, self consistent method has been developed for calculating electrostatic potential, pKa values, and titration curves based on the Multigrid Poisson-Boltzmann approach (MGPB). The method has been applied to a large (310 KD), multisubunit protein, E. coli aspartate transcarbamylase. Long range interactions have been identified in the unliganded crystal structure, and titration curves obtained with the MGPB method have been shown to agree well with experiment. These calculations have been carried out for the different states of the protein, ligated with the substrate N-phosphonacetyl-L-aspartate (PALA), inhibitor cytosine-5'-triphosphate (CTP), and both phosphonacetamide and malonate with CTP. Electrostatic modeling of additional ligated structures is being carried out to understand the changes in electrostatics due to ligation.

Preliminary MGPB analysis has also been performed on the crystal structures of wild type and mutant ferritins. The X-ray crystal structure of ornithine transcarbamylase (OTCase) in complex with its bisubstrate analog, N-(phosphonacetyl)-L-ornithine (PALO), has been solved. The crystal structural determination of wild type human OTCase and several mutants are in progress. Modeling electrostatic effects in these structures helps give an in depth understanding of their roles in driving conformational change, catalysis, and regulation.

This information is available in alternative formats upon request by individuals with disabilities. Please send email to alt-format@msi.umn.edu or call 612-624-0528.

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