Density functional studies on herpes simplex virus type 1 thymidine kinase–substrate interactions: The role of Tyr-172 and Met-128 in thymine fixation
✍ Scribed by F. Alber; O. Kuonen; L. Scapozza; G. Folkers; P. Carloni
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- English
- Weight
- 192 KB
- Volume
- 31
- Category
- Article
- ISSN
- 0887-3585
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✦ Synopsis
The enzyme herpes simplex virus type 1 thymidine kinase (HSV1 TK) salvages thymidine into the DNA metabolism of the virus. In the active site, 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 investigate the nature of the thymine-enzyme pocket interactions, we have carried out density functional theory calculations with gradient-corrected exchange-correlation functionals of models of the thymine-HSV1 TK adduct. Our calculations indicate that the role of Met-128 in the substrate fixation is purely steric and hydrophobic, while the substrate-Tyr-172 interaction is essentially electrostatic in nature. These findings are completely consistent with the available catalytic properties of mutants on the 128 position.