Adaptively Recognizing Parallel-Stranded Duplex Structure for

Zhejiang, China. ‡Department of Chemistry, Taiyuan Normal University, Taiyuan 030031, China. ¶Langzhong People's Hospital, Langzhong 637400, Sichua...
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Adaptively Recognizing Parallel-Stranded Duplex Structure for Fluorescent DNA Polarity Analysis Mei-Yun Ye, Rui-Tao Zhu, Xiang Li, Xiao-Shun Zhou, Zheng-Zhi Yin, Qian Li, and Yong Shao Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.7b02467 • Publication Date (Web): 16 Aug 2017 Downloaded from http://pubs.acs.org on August 18, 2017

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Analytical Chemistry

Adaptively Recognizing Parallel-Stranded Duplex Structure for Fluorescent DNA Polarity Analysis Mei-Yun Ye,† Rui-Tao Zhu,‡ Xiang Li,¶ Xiao-Shun Zhou,† Zheng-Zhi Yin,§ Qian Li,¥ and Yong Shao*,† †

Institute of Physical Chemistry, College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004, Zhejiang, China ‡ Department of Chemistry, Taiyuan Normal University, Taiyuan 030031, China ¶ Langzhong People’s Hospital, Langzhong 637400, Sichuan, China § College of Biological, Chemical Sciences and Engineering, Jiaxing University, Jiaxing 314001, Zhejiang, China ¥ Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China *E-mail: [email protected]. Fax: 86 579 82282595 ABSTRACT: Besides the canonical Watson-Crick (WC) linked antiparallel-stranded duplex (aps-DNA), DNA is also able to form bioactive parallel-stranded duplex (ps-DNA) with the two involving strands adopting the equal 5'-3' polarity. Discriminating psDNA from aps-DNA with an ideal selectivity is more challenging because of their comparable duplex topologies. Herein, we designed a unique probe of HPIN to fluorescently recognize ps-DNA but to keep an almost nonfluorescent response in binding with aps-DNA. The success of the Hoogsteen hydrogen bonding pattern in lighting up the HPIN fluorescence over the reverse WatsonCrick (rWC) one suggests the critical role of HPIN in structurally adaptive recognition to the strand polarity-determined basepairing peculiarity. The turn-on fluorescence should result from restriction of the HPIN cis/trans isomerization upon the adaptive Hoogsteen base pair binding. Such high performance in recognizing ps-DNA against aps-DNA demonstrates the promising applications of HPIN in developing unique DNA polarity-based sensors.

molecular crowding,17,26,27 just suggesting the promising ps-DNA applications in variant sensors. This also requires a reliable ligand to directly report the strand polarity in a label-free manner.28 In this work, according to the aps- and ps-DNA structures, we first develop a fluorescent 2-naphthol derivative HPIN (Scheme 1). Structurally, this ligand (the relative orientation of the cyclic system in HPIN was DFT optimized) was so designed to harmonize only with the base pairing orientation of ps-DNA but to be potentially discrepant with that of aps-DNA (Scheme 1). We termed this ligand as structurally adaptive probe. Expectedly, its specific ps-DNA binding follows a turn-on fluorescent response against the background emission with the aps-DNA binding. We first tested the bindings of HPIN with the 15-mer ps-DNA1 and its counterpart aps-DNA1 (Table S1 for sequence). Note that except for the polarity, these two DNAs have an identical sequence context. As shown in Figure 1A, ps-DNA1 can form the ps-DNA duplex structure at pH 5.5 with its melting temperature (Tm) at about 29.5 oC via the Hoogsteen hydrogen bonding as reported previously with this sequence (Scheme 1),1,18 while addition of excess of HPIN results in the Tm increasing to 31.6 oC. However, the same HPIN concentration slightly destabilizes apsDNA1 with Tm shifting from 40.5 to 39.1 oC. These results suggest that the HPIN binding behavior with the ps-DNA duplex is apparently different from the aps-DNA binding. More interestingly, ps-DNA1 significantly switches on the HPIN fluorescence, as opposed to the almost nonfluorescent response for aps-DNA1 (Figure 1B and C). Such distinguishing of psDNA1 over aps-DNA1 can be even visualized by the naked eye as the bright green fluorescence occurs only to ps-DNA1 solution under UV illumination (Inset of Fig. 1B). Note that this is the first report on the fluorescent probe with such high performance in discriminating ps-DNA from its counterpart aps-DNA. The HPIN

Different from the antiparallel-stranded polarity in the canonical duplex DNA collected by the Watson-Crick hydrogen bonding, the parallel-stranded orientation can shape the duplex as well as triplex and tetraplex formation according to molecularity. 1 - 5 Noncanonical base pairing patterns including the Hoogsteen, reverse Watson-Crick, and reverse Hoogsteen hydrogen bondings are believed to bring these unique structures. Relative to the parallel-stranded duplex, many efforts have been made to develop various ligands to stabilize and selectively target the triplex and tetraplex structures6-10 due to the discovered bioactivities.11-13 Of these, the developed fluorescent ligands specifically targeting these structures give potential applications in exploring highperformance sensors and advancing diagnosis/therapy techniques for gene-related diseases via the straightforward readout.8,9 Although being less stable than the antiparallel-stranded DNA duplex (aps-DNA), parallel-stranded DNA duplex (ps-DNA) is believed to still exist in loops and regions of trinucleotide repeats for regulation of cell process and evolution of neurodegenerative diseases.1, 14 , 15 Various covalent modifications including, base surrogate/isomer, 16 - 18 base cross-linkage, 19 intramolecular 3'-3' or 5'-5' phosphodiester linkage, 20 and spin label, 21 have been used to investigate the structure and property of ps-DNA. Furthermore, many efforts have also been made to stabilize psDNA using exogenous ligands including actinamycin, actinomin, netropsin, distamycin, DAPI, ethidium bromide, benzimidazole and benzopyridoindole derivatives.1, 22 - 26 Unfortunately, these ligands also serve as the universal groove and intercalation binders of aps-DNA. Accordingly, relative to the fruitful reports on ligands that can selectively target triplex and tetraplex structures, there is still a great challenge to design a ligand specific for ps-DNA against aps-DNA. Meanwhile, the ps-DNA formation is more sensitive to sequence, pH, metal ion, and

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base pairs of ps-DNA1, since in the presence of destabilizing factors (such as pH increasing used in this work), the terminal base pairs should be less stable than the central ones.21,32 The Job’s plot analysis revealed a 1:1 binding of HPIN with ps-DNA1 (Figure S4). The Hoogsteen base pair at the 3' end should be the main HPIN binding site, since the Hoogsteen base paring at this end is stronger when compared to that at the 5' end.33

excitation band upon binding with ps-DNA1 exhibits several sharp peaks within 460-485 nm, and the emission band shows a small Stokes shift relative to the excitation band. This feature in excitation band is different from HPIN free only in pure DMF (Figure S1). Therefore, the ps-DNA1 binding of HPIN should restrain rotation of the 2-aminophenol group with respect to the naphthalene moiety via the molecular rotor mechanism of cis/trans isomerization.29 HPIN should have a strong binding with the base pairs in ps-DNA via a structurally adaptive stacking because of the similar orientation of the bicyclic frame with the Hoogsteen base pair in comparison to that in aps-DNA (Scheme 1), as confirmed in the Tm experiments.

Scheme 1. Watson-Crick (left) and Hoogsteen (middle) hydrogen bonding patterns of aps-DNA and ps-DNA. The dotted lines show the geometrically symmetric axis of the bicycles by keeping the orientation of the monocycle very similar to the paired pyrimidine to suggest the structurally adaptive binding of HPIN with the Hoogsteen base pairs via efficient stacking because of their similar orientations. Besides the chemical structure of HPIN (top-right), also shown is the DFT optimized structure (bottom-right).

To confirm the molecular rotor contribution to the nonradiative relaxation of HPIN free in solution after excitation, we tested the effect of solvent viscosity on the HPIN fluorescence using the frequently used viscosity probe, DCVJ, as control in mixture solvents of glycerol and methanol.30,31 Expectedly, we found that as DCVJ, HPIN also exhibits a fluorescence behavior that is positively correlated to viscosity (Figure S2). Increasing the glycerol content from 0% to 90% results in 19.4 and 20.5 times higher fluorescence for HPIN and DCVJ, respectively. Therefore, HPIN, serving as a newly synthesized molecular rotor, can fluorescently recognize the ps-DNA duplex. The ps-DNA involving the G/C Hoogsteen base pairs is well known to be more stable upon protonating the N3 of the base C in acidic solution.16-20 We examined the pH dependence of HPIN in binding with aps- and ps-DNA1. As shown in Figure 1D, psDNA1 brings a strong pH preference in the HPIN fluorescence. Only increasing pH to 6.2 results in the fluorescence decreasing to background. However, aps-DNA1 induces negligible fluorescence in the whole investigated pH range. On the other hand, because HPIN in aqueous solution is nonfluorescent, we added 50% DMF into the buffer solution to observe the intrinsic fluorescence and found that HPIN much weakly fluoresces until pH 7.0 (with pKa≈7.7) (Figure S3). Thus, the observed HPIN fluorescence results from its binding with ps-DNA1, not from its surviving species at acidic solution. The stability of ps-DNA1 decreases when increasing the solution pH and the Tm value at pH 6.2 is about 10 oC lower than that at pH 5.5 (19.4 versus 29.5 oC, inset of Figure 1D). At pH 6.2, the ps-DNA1 duplex population seems to be somewhat lower even in the cool temperature range of 5~12 o C, as evidenced with the elevating absorbance level at these temperatures (inset of Figure 1D). At the temperature of 20 oC for fluorescence test, there is somewhat population of ps-DNA1 still in the duplex state at pH 6.2, as suggested in the melting experiments. However, the resultantly observed non-fluorescence at this pH demonstrates that HPIN should bind at the terminal G/C

Figure 1. (A) Melting curves of 2 µM ps- (top) and aps-DNA1 (bottom) in the (a) absence and (b) presence of 20 µM HPIN at pH 5.5. (B) Fluorescence excitation and emission spectra of HPIN (1 µM) at pH 5.5 for (a) aps- and (b) ps-DNA1 (9 µM). Inset: solution photographs under UV illumination. (C) Dependence of fluorescence intensity of 1 µM HPIN at 491 nm on the (a) aps- and (b) ps-DNA1 concentrations. (D) pH effect of the HPIN fluorescence (10 µM) for (a) aps- and (b) ps-DNA1 (1 µM). Inset: raw melting curves of 2 µM psDNA1 at pH 5.5 and 6.2, respectively.

In ps- and aps-DNA1, the purine-rich strand is kept intact but the pyrimidine-rich strands are each other inverted in polarity. We then prepared ps- and aps-DNA2 by otherwise inverting the polarity of the purine-rich strands but keeping intact the polarity of the pyrimidine-rich strand (Table S1). Note that ps-DNA2 and ps-DNA1 have the same sequence context except for their opposite polarities. The favored HPIN fluorescence upon binding with ps-DNA2 is continuously kept in comparison with its counterpart aps-DNA2 (Figure S5), suggesting the perfect selectivity of HPIN in discriminating ps-DNA2 from aps-DNA2. A 1:1 binding mode of HPIN with ps-DNA2 was also estimated using the Job’s plot analysis (Figure S5). Additionally, ps-DNA3 and ps-DNA4 were again compared with their counterpart aps-DNA3 and aps-DNA4 (Table S1), respectively. DNA3 and DNA4 hold the same populations of A/T and G/C base pairs as DNA1 and DNA2, but the two strands in these ps-DNAs are both reversed in polarity and the end base pairs are otherwise changed to A/T. Similarly, ps-DNA3 and psDNA4 are still the right DNAs in efficiently lighting up the HPIN fluorescence in comparison to aps-DNA3 and aps-DNA4 (Figure S5). However, it seems that both ps-DNAs bring slightly higher emission than ps-DNA1 and ps-DNA2, most likely reflecting that the end polarity-paralleled A/T base pair should be the relatively stronger HPIN binding site than the G/C one. The Job’s plot

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Analytical Chemistry fluorescence is about 40 times lower than that obtained with the 20-mer ps-DNA5. The weak bindings of HPIN with ps-DNA6 and aps-DNA6 were also confirmed by Tm experiments because of almost invariant duplex stabilities (Figure S6). Since the thymine-rich strand has the potential via the Hoogsteen hydrogen bonding to form a triplex structure with the adenine-rich aps-DNA duplex,1-4 we then tested the fluorescence response of HPIN that was pre-incubated with aps-DNA6 upon further addition of the thymine-rich DNA6-2 strand and the adenine-rich DNA6-1 strand, respectively (Figure S7B). A more prompt increase in fluorescence was observed for DNA6-2, suggesting the possible formation of Hoogsteen hydrogen bond in favor of the HPIN binding (Inset of Figure S7B), since the thymine-rich strand has a stronger binding with the adenines in the WC base pairs via this hydrogen bond in comparison with the adenine-rich strand. 35 Note that the resultant fluorescence is very weak because of inclusion of only ten consecutive adenine and thymine bases in forming the triplex structure. We also examined another rWC-linked ps-DNA7 (Table S1) with assistance from the terminal C·C+ hydrogen bonding to form the ps-DNA duplex.5 Similarly, no switch-on fluorescence of HPIN was observed (Figure S8).

analysis also revealed a 1:1 binding mode of HPIN with ps-DNA3 and ps-DNA4 (Figure S5). In order to examine the DNA length dependence of the HPIN binding, a comparison between the 20-mer ps-DNA5 and apsDNA5 was made (Table S1). Accordingly, the turn-on HPIN fluorescence remains solely for ps-DNA5 (Figure S5). Interestingly, ps-DNA5 makes a more prompt increase in fluorescence with respect to the above-used ps-DNAs. This could be caused by the enhanced stability of ps-DNA5 with the presence of the successive G/C base pairs (Tm=49.3 oC, Figure S6).20 The Job’s plot analysis (Figure S5) also suggests the almost 1:1 binding of HPIN with ps-DNA5, most likely meaning the end base-pair binding mode. The turn-on HPIN fluorescence was used to evaluate association of the two strands composed of the ps-DNA duplex. As shown in Figure 2A, gradual addition of DNA1-py strand into the DNA1-pu solution (they are partners of the ps-DNA1 duplex) results in a gradual increase in the HPIN fluorescence, again suggesting that the HPIN fluorescence arises from its specific binding with the ps-DNA duplex. Additionally, we found that to the ps-DNA1 duplex solution, further addition of the DNA2-pu strand caused a prompt decrease in HPIN fluorescence (Figure 2B), since its strong binding with the DNA1-py strand in psDNA1 can break down the ps-duplex towards the more stable apsDNA2 duplex. This again supports the specific binding of HPIN with the ps-DNA duplex.

Figure 3. (A) Effect of 10 µM metal ions (Ca2+, Sn2+, Fe3+, Al3+, Ba2+, Ag+, Cd2+, Co2+, Cu2+, Hg2+, Mn2+, Ni2+, Pb2+, Zn2+, and Mg2+) on the HPIN fluorescence (1 µM) at pH 6.5 and 2 µM ps-DNA1. Inset: photographs of these solutions under UV illumination. (B) Ag+ concentration-dependent fluorescence response of HPIN (1 µM) at pH 6.5 and 2 µM ps-DNA1 or aps-DNA1.

Figure 2. (A) Dependence of fluorescence intensity of HPIN (1 µM) in 0.1 M PBS (pH 5.5) containing the DNA1-pu strand (4 µM) on addition of the DNA1-py strand. (B) Dependence of fluorescence intensity of HPIN (1 µM) in 0.1 M PBS (pH 5.5) containing the psDNA1 duplex (4 µM) on addition of the DNA2-pu strand.

In order to widen the pH operation range in recognizing the duplex strand polarity, we furthermore checked the HPIN fluorescence upon binding to ps-DNA1 at pH 6.5 in the presence of metal ions. At pH 6.5, due to non-protonation of cytosine, psDNA1 can’t form the stable ps-DNA duplex (Figure 1D), although the Hoogsteen paired cytosine was previously found even at pH 7.0-7.2 in triplex structures.36,37 As shown in Figure 3A, addition of 10 µM Ag+ switches on the HPIN fluorescence by more than 200 times. However, other common metal ions including Ca2+, Sn2+, Fe3+, Al3+, Ba2+, Cd2+, Co2+, Cu2+, Hg2+, Mn2+, Ni2+, Pb2+, Zn2+, and Mg2+ bring negligible changes in fluorescence. Thus, the used ps-DNA duplex without any modification can display a high Ag+ binding specificity, in comparison with the previous reports using the base-modified surrogates as the strong Ag+ binding sites.16,17,38 Such specificity can be even visualized by the naked eye with the green emission under UV illumination favored only by Ag+ (Inset of Figure 3A). The Ag+ concentration-dependent experiments (Figure 3B) further support the binding specificity of HPIN with ps-DNA against apsDNA. These results also predict a wide application of HPIN in detecting the duplex polarity under assistance of the Ag+ complexation and in advancing sensors based on the ps-DNA duplex structure. For example, as an Ag+ sensor, our method

Taking together, we can conclude that the turn-on fluorescence is the ps-DNA duplex specific, independent of the context sequence and strand length, although the precise fluorescence intensity is somewhat tuned by these factors, since they subsequently determine the stability of the local structures in psDNA.20 These results suggest potential applications of HPIN in exploring the strand polarity of DNA duplex. As manifested from these experiments, the base pairing pattern of the Hoogsteen hydrogen bond is very crucial for HPIN binding and lighting-up the HPIN fluorescence. Herein, we then checked the binding of HPIN with a 25-mer ps-DNA6 that contains alternative A/T and T/A base pairs (Table S1). Note that different from the pyrimidine-rich and purine-rich strands, this ps-DNA is collected together using the reverse Watson-Crick (rWC) hydrogen bond (Inset of Figure S7A).20,21, 34 Tm experiments (Tm=27 °C, Figure S6) indicate that ps-DNA6 can form the psDNA structure at the fluorescently investigated temperature of 20 °C. The rWC pattern is very like the canonical WC one in the base pairing orientation (Scheme 1) and thus would bring a weak HPIN binding as the WC one. Indeed, ps-DNA6 shares a same HPIN fluorescence response as occurred to its counterpart apsDNA6 (Figure S7A). Additionally, the resultant HPIN

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benefits from a background-free and turn-on response (see Table S2 for a comparison with previous reports).39 It is well known that in G-quadruplex, the Hoogsteen hydrogen bonding between guanines is the driving force to form the quartet ingredients.6 We found that the DNA and RNA G-quadruplexes with variant topologies including hybrid, chair, and parallel conformations (Table S1) are inefficient to turn on the HPIN fluorescence (Figure S9), suggesting the high selectivity of HPIN in fluorescently recognizing the ps-DNA duplex. In conclusion, the strand polarity analysis in DNA duplex with an ideal selectivity is achieved using our synthesized HPIN as the fluorescent probe. The ps-DNA duplex held together by the Hoogsteen hydrogen bonding can efficiently turn on the HPIN fluorescence, as opposed to the nonfluorescent behavior when binding to the aps-DNA duplex. This hydrogen bonding patternspecific discrimination using HPIN suggests the role of structurally adaptive recognition in the polarity analysis. This is the first report on the highly selective recognization of the duplex strand polarity. Our work will inspire more interest in developing the ps-DNA duplex-based sensors. The detailed binding mode is underway in this laboratory using theoretical computation.

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ASSOCIATED CONTENT Supporting Information Experimental details; nucleic acid sequences; fluorescence spectra; Job’s plot analysis; Tm test; G-quadruplex test. This material is available free of charge via the Internet at http://pubs.acs.org.

ORCID Yong Shao: 0000-0003-0834-6244

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This work was supported by the National Natural Science Foundation of China (Grant No. 21675142 and 21545009) and the National and Zhejiang Undergraduate Training Program for Innovation and Entrepreneurship (Grant No. 201610345011 and 2016R404008).

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