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) 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.
Alber
F
F
Department of Pharmacy, Swiss Federal Institute of Technology (ETH), Zürich, Switzerland.
Kuonen
O
O
Scapozza
L
L
Folkers
G
G
Carloni
P
P
D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites; D003198:Computer Simulation; D006860:Hydrogen Bonding; D008715:Methionine / Q000502:physiology; D008958:Models, Molecular; D018139:Simplexvirus / Q000201:enzymology*; D055672:Static Electricity; D013936:Thymidine / Q000378:metabolism*; D013937:Thymidine Kinase / Q000737:chemistry / Q000378:metabolism*; D014443:Tyrosine / Q000502:physiology; D014764:Viral Proteins / Q000737:chemistry / Q000378:metabolism*
D014764:Viral Proteins; D014443:Tyrosine; D000255:Adenosine Triphosphate; D008715:Methionine; D013937:Thymidine Kinase; D013936:Thymidine