DENSITY-FUNCTIONAL STUDIES ON HERPES-SIMPLEX VIRUS TYPE-1 THYMIDINE KINASE-SUBSTRATE INTERACTIONS - THE ROLE OF TYR-172 AND MET-128 IN THYMINE FIXATION

The enzyme herpes simplex virus type 1 thymidine kinase (HSV1 TK) salv ages thymidine into the DNA metabolism of the virus. In the active sit e, the thymine ring of the nucleoside binds in a pocket, formed by two residues, Tyr-172 and Met-128, in a sandwich-type orientation. To inv estigate the nature of the thymine-enzyme pocket interactions, we have carried out density functional theory calculations with gradient-corr ected exchange-correlation functionals of models of the thymine-HSV1 T K adduct, Our calculations indicate that the role of Met-128 in the su bstrate fixation is purely steric and hydrophobic, while the substrate -Tyr-172 interaction is essentially electrostatic in nature. These fin dings are completely consistent with the available catalytic propertie s of mutants on the 128 position. (C) 1998 Wiley-Liss, Inc.