Polymorphic G:G mismatches act as hotspots for inducing right-handed Z DNA by DNA intercalation

Abstract

DNA mismatches are highly polymorphic and dynamic in nature, albeit poorly characterized structurally. We utilized the antitumour antibiotic CoII(Chro)2 (Chro = chromomycin A3) to stabilize the palindromic duplex d(TTGGCGAA) DNA with two G:G mismatches, allowing X-ray crystallography-based monitoring of mismatch polymorphism. For the first time, the unusual geometry of several G:G mismatches including syn–syn, water mediated anti–syn and syn–syn-like conformations can be simultaneously observed in the crystal structure. The G:G mismatch sites of the d(TTGGCGAA) duplex can also act as a hotspot for the formation of alternative DNA structures with a GC/GA-5′ intercalation site for binding by the GC-selective intercalator actinomycin D (ActiD). Direct intercalation of two ActiD molecules to G:G mismatch sites causes DNA rearrangements, resulting in backbone distortion to form right-handed Z-DNA structures with a single-step sharp kink. Our study provides insights on intercalators-mismatch DNA interactions and a rationale for mismatch interrogation and detection via DNA intercalation.

Melting temperature measurement and mesoscopic evaluation of single, double and triple DNA mismatches

“…For {AgC/TgG} the experimental ndings are mixed with weak, 70 single, 71 double 72 and bifurcated hydrogen bonds. 73,74 In our case we found 27.4 meV for {AgC/TgG}, which is a strong Morse potential, comparable to an AT base pair, which would be consistent with double hydrogen bonding.…”

Melting Temperature Measurement and Mesoscopic Evaluation of Single, Double and Triple DNA Mismatches

“…For {AgC/TgG} the experimental findings are mixed with weak, 61 single, 62 double 63 and bifurcated hydrogen bonds. 64,65 In our case we found 27.4 meV for {AgC/TgG}, which is a strong Morse potential, comparable to an AT base pair, which would be consistent with double hydrogen bonding.…”

Duplexes Formed by G4C2 Repeats Contain Alternate Slow- and Fast-Flipping G·G Base Pairs

“…This feature is unique for the G 4 C 2 repeat as compared to the triplet repeats such as the G 2 C repeat associated with the fragile X syndrome, for which G•G pairs can be in the 5′CGG3′ 39,51,52 or 5′GGC3′ context 74 but not concurrently both. G•G mismatched pairs were reported to be capable of binding ions, 51,75 small molecules, 30,55,76 and proteins. 27,77 As observed in the case of binding of the MutS mismatch repair enzyme, the G•G pair undergoes a structural change in the recognition and binding process with the enzyme.…”