title: Density functional studies on herpes simplex virus type 1 thymidine kinase-substrate interactions: the role of Tyr-172 and Met-128 in thymine fixation.
abstract: 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.
authors.affiliation: Department of Pharmacy, Swiss Federal Institute of Technology (ETH), Zürich, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Alber
authors.forename: O
authors.initials: O
authors.lastname: Kuonen
authors.forename: L
authors.initials: L
authors.lastname: Scapozza
authors.forename: G
authors.initials: G
authors.lastname: Folkers
authors.forename: P
authors.initials: P
authors.lastname: Carloni
mesh_terms: 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*
chemical_list: D014764:Viral Proteins; D014443:Tyrosine; D000255:Adenosine Triphosphate; D008715:Methionine; D013937:Thymidine Kinase; D013936:Thymidine