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Specific Recognition of G-Quadruplexes Over Duplex- DNA by a Macromolecular NIR Two-Photon Fluorescent Probe Marco Deiana, Bastien Mettra, Lara Martinez-Fernandez, Leszek Mateusz Mazur, Krzysztof Pawlik, Chantal Andraud, Marek Samoc, Roberto Improta, Cyrille Monnereau, and Katarzyna Matczyszyn J. Phys. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acs.jpclett.7b02547 • Publication Date (Web): 17 Nov 2017 Downloaded from http://pubs.acs.org on November 18, 2017

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The Journal of Physical Chemistry Letters

Specific Recognition of G-Quadruplexes Over Duplex-DNA by a Macromolecular NIR TwoPhoton Fluorescent Probe Marco Deiana,a Bastien Mettra,b Lara Martinez-Fernandez,c,d Leszek M. Mazur,a Krzysztof Pawlik,e Chantal Andraud,b Marek Samoc,a Roberto Improta,c,d Cyrille Monnereau,b and Katarzyna Matczyszyna,* a

Advanced Materials Engineering and Modelling Group, Faculty of Chemistry, Wroclaw

University of Science and Technology, Wyb. Wyspianskiego 27, 50-370 Wroclaw (Poland) b

Univ Lyon, ENS de Lyon, CNRS UMR 5182, Université Lyon 1, Laboratoire de Chimie,

F69342, Lyon (France) c

Consiglio Nazionale delle Ricerche, Istituto di Biostrutture e Bioimmagini, 80134 Naples,

(Italy) d

e

LIDYL, CEA, CNRS, Université Paris-Saclay, F-91191 Gif-sur-Yvette, (France)

Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of

Sciences, Rudolfa Weigla 12, 53-114 Wroclaw (Poland) AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]

ACS Paragon Plus Environment

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ABSTRACT: The implication of guanine-rich DNA sequences in biologically important roles such as telomerase dysfunction and the regulation of gene expression has prompted the search for structure-specific G-quadruplex agents for targeted diagnostic and therapeutic applications. Herein, we report on a NIR two-photon poly(cationic) anthracene-based macromolecule able to selectively target G-quadruplexes (G4s) over genomic double-stranded DNA. In particular, the striking changes in its linear and third-order nonlinear optical properties, combined with the emergence of a strong induced electronic circular dichroism (ECD) signal upon binding to canonical and noncanonical DNA secondary structures allowed for a highly specific detection of several different G4s. Furthermore, through a detailed computational analysis we bring compelling evidence that our probe intercalation within G4s is a thermodynamically favored event and we fully rationalize the spectroscopic evolution resulting from this complexation event by providing a reasonable explanation regarding the origin of the peculiar ECD effect that accompanies it. TOC GRAPHICS


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Noncanonical DNA secondary structures play a fundamental biological role in key cellular processes.1,2 In particular, guanine-rich sequences can adopt peculiar four-stranded G-quadruplex structures (G4s) in several organisms, including human cells.3,4 G4s are currently believed to be involved in gene regulation, cell division, apoptosis and in several genetic morbidities.5-10 As a consequence, they are very attractive drug targets.9-11 Even though a number of G4-binders have been reported over the past years, the issue of achieving quadruplex over duplex specificity is still highly challenging.10 Moreover, the excitation and emission wavelengths of the overwhelming majority of the molecular probes used to target G4s are often outside the biological transparency window (BTW: 680-1300 nm) where tissue absorption, scattering and autofluorescence are present, limiting their relevance to cell cultures, and precluding their use in more realistic diagnosis environments, such as blood samples.12-14 There is therefore an urge to develop optimized quadruplex-specific fluorogenic dyes specifically and rationally designed to address the aforesaid limitations and combine the right balance of optical and biological properties.15-18 Within this framework, two-photon excited probes that fluoresce in the BTW seem ideally suited. We have recently introduced a strategy based on polymer engineering to afford NIR fluorophores that combine large two-photon brightness (product of the two-photon cross section σ2 and their fluorescence quantum efficiency φf, σ2× φf) with excellent photochemical stability and biocompatibility.19-23 Besides their attractiveness as probes for cellular and intravital twophoton fluorescence imaging, some of those fluorophores exhibited specific binding to the groove of duplex DNA, which could be significantly improved upon introduction of cationic moieties along the polymer chain.23,24


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In the present manuscript, we report on the ability of a poly(cationic) probe (Ant-PIm, Chart 1) to recognize several G4s (See Supplementary information ESI p.S3-9 for details concerning the G4 structural characterization), including the archetypical G-rich telomeric DNA sequence 22AG, hereafter (1), (5′-AG3[T2AG3]3-3′), the thrombin-binding DNA aptamer TBA (2), the modified human telomeric sequence HT (3), the 91TRF2G:RNA sequence (4), the myc-2345 G4 sequence found in the promoter regions of oncogenes (5), the Oxytricha sequence Oxy28 (6) and the cKit87up sequence located in the promoter region of the human c-kit protooncogene (7). We elucidate the nature of this mechanism and of the associated spectroscopic features through computational modeling. We show that the binding mechanism of the probe toward G4s significantly differs from that encountered in the presence of duplex-DNA (minor groove binding with Kd = 2.1 × 10-6 M) , paving the way for a new generation of specific nonlinear probes for potential in situ G4 specific detection. Chart 1. Chemical structure of Ant-PIm (n = 4-5).

Ant-PIm presents a dominant intramolecular charge-transfer (ICT) transition centered at 516 nm in buffered aqueous solution. Upon titration of Ant-PIm with 1 as well as with all the G4s used in this study both in the absence and presence of metal ions (Na+ or K+), a monotonic hypochromism of the ICT band without any substantial shift of the maximum was observed (Fig. 1A, S15A-S16A and ESI p.S10-11). This spectral modification can be ascribed to specific shortrange interactions between the hydrophobic, prone to π stacking, central anthracenyl core and the


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nucleobases of the G4s. As discussed in the following, the interaction of the transition dipole moments of the nucleobases and that of the chromophore ICT can indeed affect the spatial orientation (normally coaxial with the molecule main axis) and thus the magnitude of the latter. Interestingly, this behavior is the opposite to that found in the presence of duplex-DNA, where ICT band undergoes hyperchromism along with an initial quenching of the fluorescence signal, providing the first indication of a drastically different binding mode of the probe towards G4s.23 In contrast with the absorption changes, the steady-state emission spectrum of Ant-PIm undergoes a marked increase in the fluorescence signal along with a pronounced hypsochromic effect upon addition of 1 (Fig. 1B, S15B and S16B) as well as of the other G4s used in this study (ESI p.S10-11). Data are summarized in Table S1.

Figure 1. A) Absorption spectra of Ant-PIm in the presence of 1 in 50 mM Tris and 100 mM KCl (pH 7.2). B) Emission spectra of Ant-PIm in the presence of 1 in 50 mM Tris and 100 mM KCl (pH 7.2); λexc = 515 nm. The molar ratios (r) were: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 for curves 111, respectively.


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This evolution pattern is similar to the probe’s behavior in lower-polarity solvents, where an increase of the emission energy (i.e. blue shift) is accompanied by an increase of the fluorescence quantum yield, as confirmed by the increased measured PL lifetime tabulated in Table S3.22 This result is suggestive of probe accommodation within the hydrophobic cavity of the G4s. Within the G4 scaffolds Ant-PIm would undergo conformational and vibrational restrictions, limiting the structural reorganization in the excited state minimum (hence the decreased Stokes shift) and inhibit the non-radiative relaxation pathways (hence the increased QY and lifetime, See ESI p.S14-16 for details). These observations suggest that intercalation should be the dominant coordination mechanism in the case of the G4/Ant-PIm complex. This hypothesis was therefore tested by QM/MM calculations (computational details in ESI p.S27-S29), studying the intercalation of a simplified model of Ant-PIm (hereafter Ant-PIms, see Figure S54) and the G-quadruplex core of 1 (see Fig. 2).

Figure 2. Optimized ground state minimum for 1 (QM-green tubes; MM-black lines)+Ant-PIms (pink-tubes) complex using the QM(PCM/M052X/6-31G(d))/MM level of theory.


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The ligand (in pink in Fig. 2) and 8 guanine bases (in green in Fig. 2) are treated at the DFT level, using the M052X25,26/6-31G(d) functional and basis set, and the remaining part of the system (in black in Fig. 2) is described by AMBER27 force fields using the ONIOM28 interface in Gaussian0929. This method has been successfully applied to 1 in previous computational studies.30 Solvent effects were included by the Polarizable Continuum Model (PCM).31,32 In water solution Ant-PIms is planar (see ESI p.S30-31 and Fig. S56), and its computed absorption spectrum (Fig. 3, top) exhibits two intense electronic transitions at 610 and at 320 nm plus a weaker one at 370 nm (ESI p.S30, Table S4 and Fig. S58), in good agreement with the experimental absorption spectrum.

Figure 3. Absorption (top) and circular dichroism spectra (bottom) of Ant-PIms calculated at the PCM/TD-M052X/6-31G(d) level of theory. Our calculations predict the existence of an intercalated minimum for Ant-PIms in 1. This minimum is characterized by a perturbation of the arrangement, which, although keeping the


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quadruplex structure (Fig. 2) in line with our hypothesis, involves a slight distortion of Ant-PIms from planarity. In order to establish the influence of G4 folding parameters on the affinity of the anthracenyl derivative towards G4 quadruplex, fluorescence polarization experiments were performed on unfolded and prefolded 1 (Fig. 4).33 The relative saturation curves and the Kd values derived by nonlinear least-square fitting analysis for all the guanine-rich DNA sequences used in this study are given in Table S2 and Fig. S17-22. Although the trends of spectral changes observed upon binding to the G4s are similar, the association strength was significantly higher in the absence of metal ions (Kd = 0.6 × 10-6 M for unfolded, vs Kd(K+) = 1.6 × 10-6 M; Kd(Na+) = 4.3 × 10-6 M).

Figure 4. Fluorescence polarization saturation curves of Ant-PIm in the presence of 1 under different experimental conditions (pH 7.2). (Black squares) Ant-PIm-1 in 50 mM Tris; (red circles) Ant-PIm-1 in 50 mM Tris, 100 mM KCl; (blue triangles) Ant-PIm-1 in 50 mM Tris, 100 mM NaCl. Data shown for triplicate experiments. Red lines aim only to guide the eyes.


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We ascribe this trend to the participation of the cationic imidazolium groups distributed along the side-chains of the fluorescent polymer in nonspecific ionic long-range interactions with the phosphates of the G-quadruplex. As shown in our previous reports, such ion-pair interaction strongly contribute in enhancing the Ant-PIm overall binding affinity. Upon addition of salts in the solution, screening of the phosphates negative charge by the monovalent cations is thus expected to hinder the association process. In line with our hypothesis of an intercalation of the probe within the G4 motif, we find a smaller dissociation for the Ant-PIm-G4 (K+) than for their (Na+) counterparts; we attribute this result to the well-known larger stability of quadruplex structures in the presence of K+.7 The two-photon absorption spectra of Ant-PIm in its uncomplexed state, as well as in the presence of duplex and unfolded/prefolded 1, were measured by the two-photon excited fluorescence (TPEF) method in the range 780-920 nm. Spectra are displayed in Fig. 5A.

Figure 5. A) Two-photon absorption cross-section (σ2) of Ant-PIm in the presence of 1 in its unfolded (50 mM Tris) and prefolded (50 mM Tris with either 100 mM Na+ or K+) state and dsDNA at molar ratio (r) = 5. B) Normalized σ2 of Ant-PIm plotted as a function of 1


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concentration in its unfolded (black curve) and prefolded Na+ (red curve) or K+(blue curve) state and ds-DNA (green curve). λexc = 820 nm. As expected from the Ant chromophore symmetry, the TPA spectra are dominated by a S2 ← S0 high energy transition with the TPA maximum centered around 820/830 nm in line with the computed energy associated to this transition (Table S4).20,34 The lack of the forbidden low energy S1 ← S0 transition (at λ ˃ 880 nm) excludes breaking of the molecule’s symmetry and indicates that Ant-PIm in solution exists in a single planar/centrosymmetric conformation (Fig. S24). The TPA cross-section magnitude was found to follow the order: Ant-PIm-duplex ˃ AntPIm (free) ˃ Ant-PIm-1 (no salt) ˃ Ant-PIm-1 (Na+) ˃ Ant-PIm-1 (K+). To assess and understand the binding mode of Ant-PIm towards 1 the methodology recently developed by Goodson and co-workers was used.35,36 Their model relates the changes in the dye transition dipole moment to its orientation with respect to the DNA axis. As depicted in Fig. 5B, similarly to linear absorption, the magnitude of the TPA cross-section is consistently reduced by the addition of quadruplex 1 regardless of the presence of metal ions in solution consistent with an intercalative binding process. In the presence of DNA duplex, Ant-PIm σ2 instead increased in line with its groove binding mode.23 This finding strongly supports our proposal that Ant-PIm intercalates within the quadruplex structure. Stacking to the external tetrad and/or groove binding are indeed expected to favor dyes aggregation and, due to the close proximity of their dipole moments, an increase of σ2. Actually, this is exactly the behavior found for Ant-PIm-duplex complexation. At the opposite, intercalation, due to the nearest neighbor exclusion principle, hamper a close approach between the dyes and therefore induces a decrease of the σ2 values.


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Noteworthy, an opposite trend is found for the molecular brightness (σ2 × φf), (see Figure S25) of Ant-PIm. As a result of its strong fluorescence enhancement, a relatively high action cross-section of ca. 300 GM is achieved upon G-quadruplex binding. This value is twice as large as that achieved upon ds-DNA complexation, and shows that Ant-PIm is particularly suitable for specific G-quadruplex detection. The intercalating binding mode of Ant-PIm within G4 structures was definitely confirmed through circular dichroism measurements (see ESI p.S4-9 for details concerning the effective stability of the G-quadruplexes).37 As depicted in Fig. 6 and in Fig. S27-32, addition of Ant-PIm to unfolded and prefolded G4s resulted in the appearance of a well-structured negative induced circular dichroism (ICD) band, whose position and shape corresponded exactly to those of the main ICT band in Ant-PIm (Fig. S26), in striking contrast with what we observed in previous work involving the same probe with ds-DNA.

Figure 6. Representative CD spectra of the complexation between Ant-PIm and 1 in its A) unfolded, B) prefolded (Na+) and C) (K+) state recorded in the range 300-570 nm. Experiments were conducted at different molar ratios (r) ranging from 0 to 7.


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Importantly, the ICD signal was found proportional to the Ant-PIm concentration, which rules out any aggregation process which is, instead, likely to occur for external stacking or groove binding modes (known to give rise to nonlinear strong exciton CD signals and additional higher order splitting) as a source for the observed phenomenon.38-40 By analogy with previously reported data, this behavior thus constitutes a definitive evidence of the ability of the anthracenyl derivative to intercalate within the G4s.23,37 However, the ICD bands originated upon complexation of Ant-PIm with the sequences 1, 3 and 6 (Fig. S6A, S28A and S31A) in the absence of metal ions strongly differ in term of structuration and saturation than respect to that encountered with the G-rich oligonucleotides 2, 4, 5 and 7 (Fig. S27A, S29A, S30A and S32A) within the same experimental conditions. These differences can be explained based on the different topologies that these sequences adopt in salt-deficient environments. Indeed, while the human telomeric DNA sequence forms an unstructured single-stranded geometry when not coordinated with metal ions41, promoter G4s such as myc-2345 (5) and cKit87up (7) fold into parallel G4 conformations with three double-chain-reversal loops bridging G-quartet layers even in the absence of stabilizing ions.42 It turns out, that Ant-PIm in the presence of unstructured G4-motifs not octa-coordinated with Na+ or K+ has a strong tendency to partially fold these motifs into G4-arrangements by stacking on their tetrads and leaving the cationic moiety exposed to solvent enabling to interact with the phosphate groups whereas, in the presence of partially or well-structured G4-assemblies Ant-PIm undergo intercalation. The ability of Ant-PIm to operate as a G4 stabilizing ligand can be confirmed by looking at the impact that our fluorophore has on the thrombin-binding aptamer TBA (2) (Fig. S36-S38) which is known to form a chairlike intramolecular anti-parallel G4 in the presence of metal ions.43 Indeed, when Ant-PIm is added to TBA in its unfolded state (Fig. S36) a conformational transition similar to this found for


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the same sequence when coordinated with Na+ and K+ (Fig. S37 and S38) supports the ability of the probe to induce fully structuration of the TBA anti-parallel morphology. Additional QM/MM calculations indeed shed some light on the origin of the observed ICD features. These calculations show that, while the free Ant-PIms does not present any specific ECD signature, the appearance of two intense negative features in the ECD spectrum is a distinctive signature associated to the distortion of Ant-PIms planarity when it complexes with 1 (Fig. 3, bottom). At the same time the intercalation of Ant-PIms is mirrored by a decrease of the intensity of the ECD peaks in the blue part of the spectrum (Fig. S59 in the ESI), which corresponds to contribution of 1. Those theoretical predictions were indeed fully verified experimentally (Fig. S34). To our knowledge, such ligand intercalation in G4s is quite an exotic feature of our probe, since the majority of the quadruplex binders operate by grooves or end-stack binding with the G4s.7 It is worth noting that this feature makes it possible to probe the presence of G4s using ECD spectroscopy as a particularly selective and discriminating analytical tool. In conclusion, this work describes the application of a water-soluble NIR two-photon fluorophore based anthracenyl scaffold to selectively target G-quadruplexes over duplex-DNA. In particular, the striking changes in its linear and nonlinear optical properties upon binding to canonical and noncanonical DNA secondary structures, which were rationalized through a thorough computational study, constitute a significant improvement over other classical TPA DNA-binders (e.g. the archetypical intercalator ethidium bromide and the minor groove binder Hoechst 33342).44,45 Even more relevant, the intense CD signal specifically observed on the latter chromophore CT band offers a straightforward means to definitely confirm quadruplex complex formation. The relative ease of synthesis of this probe makes it amenable to chemical modification capable of producing greater signal differentiation between G4s; in particular,


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owing to the documented influence of the polymer cationic groups on the binding process, substitution of the imidazolium side groups by other cationic moieties (ammonium, phosphonium and so forth)46 could constitute a promising approach to further enhance the potential of Ant based probes towards G-quadruplex specific recognition.

ASSOCIATED CONTENT Supporting Information. Experimental procedures, morphological effects on G-quadruplex stabilization, isothermal difference spectra (IDS), absorption and steady-state fluorescence titration experiments, nonlinear analysis of the saturation curves, Time-Correlated Single Photon Counting (TCSPC), two-photon excited fluorescence (TPEF), OPA and TPA spectra, molecular brightness plot, ICD signal and absorption spectrum of Ant-PIm, circular dichroism spectra in the 220-320 nm and 300-570 nm wavelength ranges, computational details and results.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes The authors declare no competing financial interests.


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ACKNOWLEDGMENT The financial support from FNP Mistrz grant (MD, MS) NCN OPUS project DEC2013/09/B/ST5/03417 (KM, LMM) and a statutory activity subsidy from the Polish Ministry of Science and Higher Education for the Faculty of Chemistry of WUT are acknowledged. Harmonia grant UMO-2016/22/M/ST4/00275 is highly acknowledged. REFERENCES (1) Chen, Y.; Qu, K.; Zhao, C.; Wu, L.; Ren, J.; Wang, J.; Qu, X. Insights into the Biomedical Effects of Carboxylated Single-Wall Carbon Nanotubes on Telomerase and Telomeres. Nat. Commun. 2012, 3, 1074. doi: 10.1038/ncomms2091 (2) Chung, W. J.; Heddi, B.; Schmitt, E.; Lim, K. W.; Mechulam, Y.; Phan, A. T. Structure of a Left-Handed DNA G-Quadruplex. Proc. Natl. Acad. Sci. U.S.A., 2015, 112, 27292733. (3) Zhao, C.; Wu, L.; Ren, J.; Xu, Y.; Qu, X. Targeting Human Telomeric Higher-Order DNA: Dimeric G-Quadruplex Units Serve as Preferred Binding Site. J. Am. Chem. Soc. 2013, 135, 18786-18789. (4) Rodriguez, R.; Miller, K. M.; Forment, J. V.; Bradshaw, C. R.; Nikan, M.; Britton, S.; Oelschlaegel, T.; Xhemalce, B.; Balasubramanian, S.; Jackson, S. P. Small-MoleculeInduced DNA Damage Identifies Alternative DNA Structures in Human Genes. Nat. Chem. Biol. 2012, 8, 301-310. (5) Shivalingam, A.; Izquierdo, M. A.; Le Marois, A.; Vyšniauskas, A.; Suhling, K.; Kuimova, M. K.; Vilar, R. The Interactions between a Small Molecule and GQuadruplexes Are Visualized by Fluorescence Lifetime Imaging Microscopy. Nat. Commun. 2015, 6, 8178. doi:10.1038/ncomms9178


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Specific Recognition of G-Quadruplexes Over ... - ACS Publications

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