Complex between human RNase HI and the phosphonate-DNA/RNA duplex: molecular dynamics study

. 2013 Jul ; 44 () : 81-90. [epub] 20130517

Jazyk angličtina Země Spojené státy americké Médium print-electronic

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/pmid23751958
Odkazy

PubMed 23751958
DOI 10.1016/j.jmgm.2013.05.004
PII: S1093-3263(13)00093-4
Knihovny.cz E-zdroje

Our 200ns MD simulations show that even fully modified oligonucleotides bearing the 3'-O-P-CH2-O-5' (but not 3'-O-CH2-P-O-5') phosphonate linkages can be successfully attached to the surface of Human RNase H. It enables to explain that oligonucleotides consisting of the alternating 3'-O-P-CH2-O-5' phosphonate and phosphodiester linkages are capable to elicit the RNase H activity (while the 3'-O-CH2-P-O-5' phosphonates are completely inactive). Stability of the binuclear active site of Human RNase H was achieved using the one-atom model for Mg(2+) in conjunction with a polarized phosphate group of the scissile bond, which is wedged between both magnesium ions. The reference MD simulation (lasting for 1000ns), which was produced using a well-established seven-point (with dummy atoms) model for Mg(2+) led to essentially the same results. The MD run (lasting for 500ns) produced for the Thermus thermophilus Argonaute enzyme shows the transferability of our approach for the stabilization of a binuclear active site. Glu512 was bound in the T. thermophilus Argonaute active site to the 2'-OH of the nucleotide adjacent to the scissile phosphate and one of the two active-site divalent metal ions in exactly the same way as Glu186 in Human RNase H. Glu512 thus completes the catalytic tetrad of Argonaute.

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