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Abstract: M. Hutter Melbourne 1997

Modelling the binding position of dihydrofolate reductase ligands
using a combined QM/MM-method

Michael Hutter

School of Chemistry F11
University of Sydney

NSW 2006


The position of the strong inhibitor methotrexate in dihydrofolate reductase was modelled using a combined QM/MM-method. The QM-part (ligand) is treated with the semiempirical AM1 hamiltonian while the MM-part (enzyme) refers to a force field like potential. The found binding sites are in good agreement with the X-ray structure of DHFR from E.coli (4DFR). For the .gamma.-carboxylate group, however, an alternative binding site towards lysine 32 was found. This is in accordance with the flexibility of this side chain which shows also the highest temperature factors in the crystal structure. Compared with the natural substrate dihydrofolate assuming the same binding mode, the electrostatic potentials on the molecules van der Waals surface differ significantly only at the 4-hydroxy group. Didydrofolate, however, is assumed to bind as the 4-keto tautomer in a binding mode having the pteridin ring rotated by about 180 degrees. This corresponding docking position was also found by the QM/MM-method and compared to that of methotrexate.
M. Hutter 05. September 1997

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