Flexibility and stabilization of Hg^II-mediated C:T and T:T base pairs in DNA duplex

Abstract

Owing to their great potentials in genetic code extension and the development of nucleic acid-based functional nanodevices, DNA duplexes containing HgII-mediated base pairs have been extensively studied during the past 60 years. However, structural basis underlying these base pairs remains poorly understood. Herein, we present five high-resolution crystal structures including one first-time reported C–HgII–T containing duplex, three T–HgII–T containing duplexes and one native duplex containing T–T pair without HgII. Our structures suggest that both C–T and T–T pairs are flexible in interacting with the HgII ion with various binding modes including N3–HgII–N3, N4–HgII–N3, O2–HgII–N3 and N3–HgII–O4. Our studies also reveal that the overall conformations of the C–HgII–T and T–HgII–T pairs are affected by their neighboring residues via the interactions with the solvent molecules or other metal ions, such as SrII. These results provide detailed insights into the interactions between HgII and nucleobases and the structural basis for the rational design of C–HgII–T or T–HgII–T containing DNA nanodevices in the future.

HgII binds to C–T mismatches with high affinity

“…Consistent with this, C–T mismatches exhibited approximately 10-fold higher rate constants of Hg II association and dissociation as compared to T–T mismatches, suggesting a kinetically less stable, more solvent-exposed coordination site of Hg II in C–Hg II –T than in T–Hg II –T. Taken together, these observations are consistent with a recently reported X-ray structure of a C–Hg II –T base pair in an A-form duplex DNA ( 9 ) where the metal ion was unexpectedly bound to the exocyclic amine ( N4 ) of a deprotonated cytosine residue and to the N3 of a deprotonated thymidine (Figure 7 ). Additional studies using 15 N-NMR ( 4 , 5 ) will be required to determine if one or both of these metal binding modes are present in duplex DNA containing C–Hg II –T base pairs in solution.…”

“… ( A ) Structure of proposed, hypothetical ( N3 )C–Hg II –( N3 )T coordination complex ( 36 ) based upon structural analogy with T–Hg II –T ( 4 , 37 ) and C–Ag I –C ( 5 , 8 , 10 ). ( B ) Structure of ( N4 )C–Hg II –( N3 )T coordination complex recently observed in an X-ray crystal structure of a short, A-form duplex DNA containing a C–T mismatch bound to Hg II ( 9 ). (R, R' = duplex DNA).…”

“…A wide variety of other metallated base pairs have been observed in crystals of non-B-form nucleic acids ( 8–10 ). For example, a G–Au III –C base pair was observed in the initiation site of HIV-1 RNA ( 11 ), and a C–Hg II –T base pair was found in short, A-form duplex DNA where the metal ion was unexpectedly bound to the exocyclic amine ( N4 ) of a deprotonated cytosine residue and to the N3 of a deprotonated thymidine ( 9 ). A solid-state ‘wire’ containing C–Ag I –C, G–Ag I –G, G–Ag I –C, and T–Ag I –T base pairs was recently reported ( 8 ), as well as a short, non-helical DNA structure containing one G–Ag I –G and two C–Ag I –C base pairs ( 10 ).…”

QM and QM/MM umbrella sampling MD study of the formation of Hg(II)–thymine bond: Model for evaluation of the reaction energy profiles in solutions with constant pH

“…Superior occupation of the N3 site is, however, not sustainable over the whole pH range. Such a metal migration between heteroatoms was recently suggested for Hg(II) complexes in papers as well as for Pt(II) complexes . In this contribution, we clearly show that the Hg 2+ cation is coordinated to the N3 site of T for pH larger than 5.…”

A DNA Structure Containing AgI‐Mediated G:G and C:C Base Pairs

“…Hg II can interact with both T:T and C:T mispairs to give T‐Hg II ‐T (the first identified metallo base pair) and C‐Hg II ‐T pairs . The formation and detailed conformations of these Hg II ‐mediated base pairs have been structurally characterized by others and our group very recently. Compared to Au III and Hg II , Ag I is known to be more flexible in coordinating with nucleobases through C‐Ag I ‐C, G‐Ag I ‐G, and C‐Ag I ‐A pairs .…”