Molecular Recognition at the Electronic Level
EMSL Project ID
18593a
Abstract
The goal of the proposed research is to develop a new approach to understanding biochemical macromolecular recognition of cofactors and substrate molecules through a graphical display of HOMOs and LUMOs; that is by displaying the frontier orbitals of interacting molecules. The systems of choice are biological macromolecules for which quality single crystal studies have been reported combined with substrate molecules for which either high resolution crystal structures can serve as starting models or for which theoretical calculations can produce relevant models. There are two systems selected for the initial study. One is the tetracycline antibiotics for which very high resolution crystal structures are available as are crystal structures with relevant proteins and/or DNA models are known. The other is Green Fluorescent Protein (GFP) for which an extensive series of crystal structures are available some of which show different reaction mechanisms that the wild type protein.Preliminary calculations on the tetracyclines have revealed very different distributions of HOMOs and LUMOs depending on the solvent system crystals are grown from (Stezowski, J.J.; J. Am. Soc., (1976) 98, 6012-6018). The Tet-Repressor protein, for which a crystal structure of the 7-chlorotetracycline complex with Mg2+ has been reported (Hinrichs, W.; Kisker, C.; Dueval, M.; Mueller, A.; Tovan, K.; Hillen, W.; Saenger,.; Science (1994) 264, 418-420), is a very attractive target system for further study. In the published model an incorrect tetracycline molecular model was used producing inaccurate hydrogen bonding interactions. Calculations in our laboratory have revealed a significantly different conformation of 5-hydroxytetracycline molecule when complexed with Mg2+ than those of the free base in either its nonionized form or in the zwitterionic form or for the fully protoated cation. Some preliminary calculations with the tetracycline molecule in a highly clipped binding pocket demonstrate that high level ab initio calculations are informative, but more computational power is needed if maximum value is to be obtained from the study. In collaboration with Sotiris S. Xantheas, we propose to use NWChem software that is pn hand at EMSL to expand the size of the model used for the bining pocker. The binding pocket can be constructed from the available Tet-repressor - 7-chlorotetracycline structure referred to above using INSIGHT II on our local SGI Onyx computer.
Similarly with sufficient computational power, calculations of electronic properties of the GFP mutants with different catalytic properties have the potential to reveal not only new insights into intermolecular interactions but also improved understanding of reaction mechanisms in organic chemistry.
Sotiris has suggested that we request 50,000 node hours on mpp2. Joint publication of results is anticipated within 12 months or less.
Project Details
Project type
Exploratory Research
Start Date
2006-07-21
End Date
2007-08-07
Status
Closed
Released Data Link
Team
Principal Investigator