We present a theoretical study of the interactions of viral herpes simplex type 1 thymidine kinase with its substrate, thymidine. Density functional theory calculations with gradient-corrected exchange-correlation functionals are carried out for various models of the nucleoside binding site-substrate adducts. Our calculations indicate that (i) Coulombic interactions play an important role in the substrate binding, (ii) the role of Met 128, an important residue in the active site cavity of the enzyme, is purely steric and hydrophobic, in agreement with very recent site-mutagenesis experiments (Folkers, G. et al., in preparation), and (iii) transferring a proton from Tyr 172 in the active site to the substrate may be a key step in the enzyme's mechanism of action.
By: F. Alber (ETH, Switz.), O. Kuonen (ETH, Switz.), L. Scapozza (ETH, Switz.), G. Folkers (ETH, Switz.) and P. Carloni
Published in: RZ2897 in 1996
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