Journal Article

FZJ-2018-01745

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A Strategically Located Arg/Lys Residue Promotes Correct Base Paring During Nucleic Acid Biosynthesis in Polymerases

Genna, V. ; Carloni, P.FZJ* ; De Vivo, M. (Corresponding author)FZJ*

2018
American Chemical Society Washington, DC

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Please use a persistent id in citations: doi:10.1021/jacs.7b12446

Abstract: Polymerases (Pols) synthesize the double-stranded nucleic acids in the Watson–Crick (W–C) conformation, which is critical for DNA and RNA functioning. Yet, the molecular basis to catalyze the W–C base pairing during Pol-mediated nucleic acids biosynthesis remains unclear. Here, through bioinformatics analyses on a large data set of Pol/DNA structures, we first describe the conserved presence of one positively charged residue (Lys or Arg), which is similarly located near the enzymatic two-metal active site, always interacting directly with the incoming substrate (d)NTP. Incidentally, we noted that some Pol/DNA structures showing the alternative Hoogsteen base pairing were often solved with this specific residue either mutated, displaced, or missing. We then used quantum and classical simulations coupled to free-energy calculations to illustrate how, in human DNA Pol-η, the conserved Arg61 favors W–C base pairing through defined interactions with the incoming nucleotide. Taken together, these structural observations and computational results suggest a structural framework in which this specific residue is critical for stabilizing the incoming (d)NTP nucleotide and base pairing during Pol-mediated nucleic acid biosynthesis. These results may benefit enzyme engineering for nucleic acid processing and encourage new drug discovery strategies to modulate Pols function.

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Contributing Institute(s):

1. Computational Biomedicine (IAS-5)
2. Computational Biomedicine (INM-9)

Research Program(s):

1. 574 - Theory, modelling and simulation (POF3-574) (POF3-574)

Appears in the scientific report 2018

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Database coverage:
; BIOSIS Previews ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; Ebsco Academic Search ; IF >= 10 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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