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Density functional studies on herpes simplex virus type 1 thymidine kinase–substrate interactions: The role of Tyr‐172 and Met‐128 in thymine fixation
Author(s) -
Alber F.,
Kuonen O.,
Scapozza L.,
Folkers G.,
Carloni P.
Publication year - 1998
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/(sici)1097-0134(19980601)31:4<453::aid-prot11>3.0.co;2-e
Subject(s) - thymine , thymidine kinase , thymidine , herpes simplex virus , steric effects , dna , nucleoside , enzyme , active site , chemistry , stereochemistry , substrate (aquarium) , nucleoside analogue , biochemistry , biology , virus , virology , ecology
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. Proteins 31:453–459, 1998. © 1998 Wiley‐Liss, Inc.