title: Structural basis for the role of LYS220 as proton donor for nucleotidyl transfer in HIV-1 reverse transcriptase.
abstract: Biochemical studies by Castro et al. have recently revealed a crucial role for a general acid in the catalysis of nucleic acid transfer in distinct classes of polymerases. For HIV-RT LYS220 was identified as proton donor. This was unanticipated from a structural point of view, since in all ternary crystal structures of HIV-RT LYS220 are too distant from the active site to fulfill this role. In this work molecular dynamics simulations were used to reveal the dynamics of HIV-RT and to provide structural evidence for the role of LYS220. During a 1μs molecular dynamics simulation LYS220 migrates toward the active site and occupies several positions enabling direct and water mediated proton transfer towards pyrophosphate. A combination of quantum mechanical and molecular mechanics methods was used to validate the different modes of interaction.
authors.affiliation: Departement of Chemistry and INPAC Institute of Nanoscale Physics and Chemistry, Katholieke Universiteit Leuven, Belgium. servaas.michielssens@chem.kuleuven.be
authors.forename: Servaas
authors.initials: S
authors.lastname: Michielssens
authors.forename: Samuel L C
authors.initials: SL
authors.lastname: Moors
authors.forename: Mathy
authors.initials: M
authors.lastname: Froeyen
authors.forename: Piet
authors.initials: P
authors.lastname: Herdewijn
authors.forename: Arnout
authors.initials: A
authors.lastname: Ceulemans
mesh_terms: D018360:Crystallography, X-Ray; D054303:HIV Reverse Transcriptase / Q000737:chemistry* / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D009696:Nucleic Acids / Q000737:chemistry / Q000378:metabolism*; D011522:Protons; D011789:Quantum Theory
chemical_list: D009696:Nucleic Acids; D011522:Protons; D054303:HIV Reverse Transcriptase; D008239:Lysine