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Please use this identifier to cite or link to this item: http://hdl.handle.net/2262/65712

Title: Structural basis for the role of LYS220 as proton donor for nucleotidyl transfer in HIV-1 Reverse transcriptase
Keywords: HIV reverse transcriptase
QM/MM
Molecular Dynamics
Protein dynamics
Enzymatic catalysis
Issue Date: 30-May-2011
Publisher: Elsevier
Abstract: 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 is 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 1 μs 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.
Graphical abstract Research highlights ►A structural explanation for the catalytic role of Lys220 in HIV-RT is offered using molecular dynamics simulations. QM/MM optimizations are used to asses the quality of the structures found on a quantum mechanical potential. The results are compared to the ensemble of available crystal structures of this protein.
URI: http://hdl.handle.net/2262/65712
ISSN: 03014622 (ISSN)
DOI: 10.1016/j.bpc.2011.03.009
Rights: 2010
Affiliation: Departement of Chemistry and INPAC Institute of Nanoscale Physics & Chemistry, Katholieke Universiteit Leuven - Leuven--> - BELGIUM (Michielssens, Servaas)
BELGIUM (Michielssens, Servaas)
Departement of Chemistry and INPAC Institute of Nanoscale Physics & Chemistry, Katholieke Universiteit Leuven - Leuven--> - BELGIUM (Moors, Samuel L.C.)
Rega Institute for Medicinal Research, Katholieke Universiteit Leuven - Leuven--> - BELGIUM (Froeyen, Mathy)
Rega Institute for Medicinal Research, Katholieke Universiteit Leuven - Leuven--> - BELGIUM (Herdewijn, Piet)
Departement of Chemistry and INPAC Institute of Nanoscale Physics & Chemistry, Katholieke Universiteit Leuven - Leuven--> - BELGIUM (Ceulemans, Arnout)
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