On the Helical Structure of Guanosine 5′-Monophosphate Formed at pH 5: Is It Left- or Right-Handed?

Wu, Gang; Kwan, Irene C. M.; Yan, Zhimin; Huang, Yining; Ye, Eric

doi:https://doi.org/10.1155/2017/6798759

Journal of Nucleic Acids

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G-quadruplexes

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Volume 2017 | Article ID 6798759 | https://doi.org/10.1155/2017/6798759

On the Helical Structure of Guanosine 5′-Monophosphate Formed at pH 5: Is It Left- or Right-Handed?

Gang Wu,¹Irene C. M. Kwan,¹Zhimin Yan,²Yining Huang,²and Eric Ye³

Academic Editor: Gary Parkinson

Received24 Jul 2017

Accepted11 Oct 2017

Published02 Nov 2017

Abstract

Early X-ray fiber diffraction studies have established that the spontaneous gel formation of guanosine 5′-monophosphate (5′-GMP) under slightly acidic conditions (e.g., pH 5) results from self-assembly of 5′-GMP into a helical structure in which hydrogen-bonded guanine bases form a continuous helix with 15 nucleotides per 4 turns. For more than five decades, the sense of this helix is believed to be left-handed. Using multinuclear solid-state NMR and IR spectroscopic methods, we have finally determined the long-missing structural details of this helix. First, we found that this 5′-GMP helix is right-handed containing exclusive C3′-endo sugar puckers. Second, we showed that the central channel of this helix is free of Na⁺ ions, which is in sharp contrast to the helix formed by 5′-GMP at pH 8 where the central channel is filled with Na⁺ ions.

1. Introduction

Gel formation of guanosine 5′-monophosphate (5′-GMP) under slightly acidic conditions (e.g., pH 5) was first discovered by Bang in 1910 [1]. However, it was not until 50 years later that the structural basis of such 5′-GMP gel was examined. In 1962, Gellert et al. [2] used X-ray fiber diffraction data to show that different GMP isomers form different helical structures. For 3′-GMP gel, the helical structure is formed by successive stacking of planar hydrogen-bonded guanine tetramers now known as the G-quartets on top of each other. For 5′-GMP gel formed at pH 5, in contrast, the planar (disc-like) G-quartet is broken at one side forming a lock-washer-like structure which is further hydrogen bonded into a continuous helix; see Figure 1. In 1975, Sasisekharan et al. [3] further investigated the helical structure formed by 5′-GMP at pH 5 (i.e., 5′-GMP gel) and reported atomic coordinates for a left-handed 15/4 helix model. However, these authors also noted in the paper that “[b ]ecause the helix is not constrained by a continuous covalently bonded backbone, both right- and left-handed helices of the 15/4 model can be constructed. Although stereochemically quite different, they are both acceptable. …For arbitrary reasons, we have selected for detailed examination a left-handed helix….” Therefore, it appears that, on the basis of the original fiber X-ray diffraction data alone, there is no particular reason to favor a left-handed helix over a right-handed one. However, this arbitrary choice of the helical structure has been overlooked in the literature so that, even in classic treatises of nucleic acid structures such as that by Saenger [4], this helix is described as left-handed. It is also clear from the study of Sasisekharan et al. [3] that whether the acidic 5′-GMP helix is left- or right-handed depends critically on the sugar pucker conformation. That is, a C2′-endo sugar pucker would favor a left-handed helix but a C3′-endo conformation would result in a right-handed helix. However, because 5′-GMP gels are difficult to study with common spectroscopic techniques, the question regarding its exact helical structure has never been fully addressed.

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(b)

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In 2009, we used solution NMR techniques to obtain structural details of the helix formed by 5′-GMP at pH 8 [5]. As shown in Figure 1, the physical appearance of the 5′-GMP solution depends critically on the pH. At pH 8, the 5′-GMP solution appears as a normal liquid, whereas, at pH 5, it becomes a gel. The key findings of our earlier study of the 5′-GMP helix formed at pH 8 are as follows. First, the central structural motif of the helix is the disc-like G₄. Second, the 5′-GMP molecules take alternating C2′-endo and C3′-endo sugar pucker conformation along the helical strand. Third, the helix is right-handed. Fourth, the central channel of the helix is filled with Na⁺ ions each being sandwiched between two disc-like G₄s. In contrast, as Sasisekharan et al. [3] proposed, the central structural motif of the helix formed by 5′-GMP at pH 5 is a lock-washer-like G₄ structure, as illustrated in Figure 1. However, other details about this helix are not known. Since 5′-GMP forms gel at pH 5, conventional solution NMR techniques are not applicable. In this work, we applied solid-state NMR and IR methods to obtain structural details about the helical structure formed by 5′-GMP at pH 5 (5′-GMP gels). In particular, we set out to address key questions concerning sugar pucker conformation, phosphate-phosphate interaction, phosphate-base interaction, and metal ion binding environment around the helical structure.

2. Experimental Sections

Hydrated disodium salt of guanosine 5′-monophosphate (purity > 99%) was obtained from Sigma-Aldrich (Ontario, Canada). The 5′-GMP gel sample was prepared by acidifying 1.0 M Na₂(5′-GMP) aqueous solution to pH 5 with acetic acid. Before the solid-state NMR experiments, the gel was gently dried with a stream of N₂. The 1D ¹H MAS and 2D ¹H double quantum (DQ) NMR experiments were performed at 21.1 T with a Bruker 1.3 mm HX probe with a sample spinning frequency of 62.5 kHz. The back-to-back (BABA) recoupling sequence [7] was used for the ¹H DQ experiments with the excitation time being set to one rotor period. The recycle time employed was 8 s. The 2D ¹H → ³¹P HETCOR experiments were performed at 21.1 T with a Bruker 2.4-mm MAS probe. The sample spinning frequency was 33 kHz. Contact times from 0.5 to 2.0 ms were employed. Solid-state ¹³C CP/MAS NMR experiments were performed at 14.1 and 21.1 T. All ¹³C chemical shifts were referenced to that of TMS by setting the ¹³C signal of a solid sample of tetrakis (trimethylsilyl) silane (TKS) to 3.50 ppm. Solid-state ³¹P NMR experiments were performed on a Bruker Avance-600 spectrometer operating at 242.96 MHz for ³¹P. All ³¹P chemical shifts were referenced to 85% H₃PO₄ (aq). Solid-state ²³Na NMR experiments were performed on a Bruker Avance-500 spectrometer operating at 132.72 MHz for ²³Na nuclei with the following parameters: sample spinning, 10 kHz; ¹H decoupling, 65 kHz; recycle time, 10 s; 64 transients. All ²³Na chemical shifts were referenced to NaCl (aq) at δ = 0.0 ppm by setting the ²³Na signal of NaCl(s) to 7.21 ppm. ²³Na REDOR experiments using the original version of the pulse sequence [8] were performed on a Varian/Chemagnetics Infinity-Plus 400 WB spectrometer operating at a magnetic field strength of 9.4 T. The ³¹P and ²³Na resonance frequencies at this field strength are 161.72 and 105.67 MHz, respectively. All MAS spectra were acquired using a Varian/Chemagnetics T3 4-mm triple-tuned MAS probe. Typical RF power levels corresponded to 180° pulse lengths of 7.0 and 7.8 μs for ²³Na and ³¹P nuclei, respectively. A total of 512 transients were accumulated for each REDOR measurement. The sample spinning rate was kept constant at Hz. The recycle delay was 0.2 s.

3. Results and Discussion

To assess the basic self-assembled structure of 5′-GMP gel formed at pH 5, we first obtained its ¹H solid-state NMR spectra under very fast MAS conditions at an ultrahigh magnetic field, 21.1 T (900 MHz for ¹H). For comparison, we also reported the corresponding ¹H NMR spectra for crystalline Na₂(5′-GMP)·7H₂O (orthorhombic). As seen in Figure 2, for the acidic 5′-GMP gel sample, the N₁H and signals appear at about 10.6 ppm, suggesting that both protons are involved in strong hydrogen bonding. The DQ signals connecting and H8 provide the most direct evidence for G₄ formation, although this feature alone cannot reliably distinguish between the planar disk-G₄ and lock-washer-G₄ motifs (vide infra). Interestingly, two N₁H signals are seen for Na₂(5′-GMP)·7H₂O (orthorhombic). This observation is consistent with the crystal structure of the compound where there are two distinct 5′-GMP molecules in the asymmetric unit [9]. This doubling of the signals is more evident in the ¹³C CP/MAS spectrum of Na₂(5′-GMP)·7H₂O (orthorhombic) (see Figure S1 in the Supporting Information, available online at https://doi.org/10.1155/2017/6798759). Furthermore, for Na₂(5′-GMP)·7H₂O (orthorhombic), the N₁H signals appear at about 13.5 ppm, whereas the corresponding N₂H signals are between 4 and 6 ppm. These observed ¹H chemical shifts are in agreement with the crystal structure of Na₂(5′-GMP)·7H₂O (orthorhombic) which shows that N₁H forms a strong hydrogen bond with ⁻O-P (the two N⋯O distances are 2.76 and 2.79 Å) and the N₂H groups are only weakly hydrogen bonded to water molecules (two N⋯ distances are 2.91 and 2.95 Å) [9]. It is interesting to note that both acidic 5′-GMP gel and Na₂(5′-GMP)·7H₂O exhibit DQ signals between H8 and H5′,5′′, consistent with the guanine base being in the anti-conformation. Now, while the ¹H solid-state NMR data confirm G4 formation for the acidic 5′-GMP gel, they provide no information about the sense of the helix.

(a)

(b)

As mentioned earlier, on the basis of modeling performed by Sasisekharan et al. [3], whether the acidic 5′-GMP helix is left- or right-handed depends critically on the sugar pucker conformation. To answer this question, we utilized a well-established approach in using ¹³C chemical shifts of the sugar carbons as a means of determining the sugar pucker conformation. In particular, Harbison and coworkers [10, 11] showed that, for RNA nucleosides and nucleotides, one can combine the ¹³C chemical shifts observed for the ribose moiety into the following two canonical coordinates:Then any data point appearing in the can1-can2 plot can be used to determine the sugar pucker conformation (can1 > −6.77 for C3′-endo and can1 < −6.77 for C2′-endo) as well as the exocyclic γ-torsion angle (can2 < −16.82 for gt and can2 > −16.82 for gg). Later, Ohlenschläger et al. [12] applied this approach to analyze a total of 429 known RNA structures and showed that the reliability of this approach for purine nucleotides is 93-94% (see Figure S2 in the Supporting Information).

Figure 3(a) shows the solid-state ¹³C CP/MAS NMR spectrum of acidic 5′-GMP gel where the observed ¹³C chemical shifts for sugar carbons C1′, C2′, C3′, C4′, and C5′ are 87.9, 76.3, 69.3, 82.2, and 62.8 ppm, respectively. This assignment was further confirmed by DFT calculations on the ¹³C chemical shifts for a model 5′-GMP molecule. These values yield can1 = −6.43 and can2 = −16.67 for the acidic 5′-GMP gel. Now the fact that can1 > −6.77 and can2 > −16.82 for the acidic 5′-GMP gel strongly suggests that the sugar pucker conformation is exclusively C3′-endo with the exocyclic γ-torsion angle being in the gg conformation [10–12]; see Figure S2 in the Supporting Information. These canonical coordinates are quite different from those for Na₂(5′-GMP)·7H₂O (orthorhombic) and 5′-GMP self-assembly formed at pH 8; also see Figure S2 in the Supporting Information. This new information about the C3′-endo sugar pucker conformation means that the continuous helix of the acidic 5′-GMP gel is right-handed. To further confirm the C3′-endo sugar pucker conformation determined above, we recorded FTIR spectra for three 5′-GMP samples. Some time ago, Tajmir-Riahi [13] showed that the P-O-5′-ribose stretch frequency can be used as the signature for the sugar pucker conformation for guanylic acid and its salts: 800 cm^–1 for C3′-endo and 820 cm^–1 for C2′-endo. As seen from Figure 3(b), the acidic 5′-GMP gel sample indeed displays a peak at 800 cm^–1, confirming the aforementioned C3′-endo sugar pucker conformation. In comparison, the FTIR spectrum of the 5′-GMP self-assembly formed at pH 8 exhibits both 800 and 820 cm^–1 peaks of equal intensity. This is in agreement with the earlier observation that the helical structure of 5′-GMP formed at pH 8 consists of alternating C3′-endo and C2′-endo sugar pucker conformation [5]. For Na₂(5′-GMP)·7H₂O (orthorhombic), the observation of a peak at 820 cm^–1 is in agreement with its crystal structure where the ribose is in the C2′-endo conformation [9]. Therefore, the FTIR data shown in Figure 3(b) are fully consistent with the results on sugar pucker conformation obtained from the ¹³C chemical shift analysis. Now, combining the C3′-endo sugar pucker conformation with the helical parameters reported by Sasisekharan et al. [3], we can readily build a right-handed 15/4 helix model; see Figure S3 and Table S1 in the Supporting Information for atomic coordinates.

(a)

(b)

Since metal ion binding is an integral part of G-quadruplex formation [14–18], we further investigated how Na⁺ ions are bound to the acidic 5′-GMP helical structure. Figure 4 shows the solid-state ²³Na NMR spectra obtained for the acidic 5′-GMP gel as well as for a neutral 5′-GMP self-assembly sample for comparison. The two ²³Na NMR signals observed for the acidic 5′-GMP gel can be readily assigned: the sharp signal at 7.2 ppm is due to fully hydrated Na⁺ ions and the signal centered at −5.0 ppm is from phosphate-bound Na⁺ ions. To further confirm the phosphate-bound nature of the signal at −5.0 ppm, we performed ²³Na rotational-echo double resonance (REDOR) [8] experiments. As shown in Figure 5, the ²³Na REDOR results obtained for the acidic 5′-GMP gel are quite similar to those for neutral 5′-GMP and for double-stranded calf thymus DNA in the dry state (A-form) [19]. Thus the ²³Na REDOR results confirmed unambiguously that the ²³Na NMR signal at −5 ppm arises from Na⁺ ions bound to the phosphate group. The most striking feature in the ²³Na NMR spectrum of acidic 5′-GMP gel is the absence of any signal at ca. −18 ppm, which is the established spectral signature for Na⁺ ions residing inside a G-quadruplex channel [20–22]. This observation immediately suggests that there is no Na⁺ ion inside the central channel of the continuous helix formed by 5′-GMP at pH 5! This aspect of the helix, though totally unexpected, can be readily understood on the basis of our structural model. As seen from Figure 6, when a disc-like G₄ is twisted into a lock-washer-like G₄, the size of the central cavity surrounded by carbonyl oxygen atoms is significantly reduced. As a result, Na⁺ ions can no longer fit into this cavity. The diameter of the central channel is reduced by nearly 50% for the acidic 5′-GMP helix compared with that of the neutral 5′-GMP helix, as clearly seen from the top view of the channel shown in Figure 6. This observation is consistent with the fact that 5′-GMP gel formation at pH 5 is not sensitive to the nature of monovalent cations (Na⁺, K⁺, or ) present in solution. It is also worth noting that the helical structure of acidic 5′-GMP gel is remarkably similar to that found for 8-oxoguanosine reported recently by Giorgi et al. [23], despite the very different hydrogen bonding schemes in these two systems. Here we further comment on the role that the central cations play in G-quadruplex systems consisting planar disc-like G-quartets. While it is commonly accepted that the central cation is to reduce the repulsion between carbonyl oxygen atoms from G-quartets, it is important to point out that it is primarily the repulsions between carbonyl oxygen atoms from adjacent planar G-quartets, not from within the same G-quartet, which requires further stabilization from a cation. The main evidence for this view is the fact that whereas a cation-free or “empty” G-quartet was observed [24], an “empty” G-octamer has never been reported. Now when the helix is made of lock-washer-like G₄, there is no longer any repulsion between carbonyl oxygen atoms along the helical axis, thus making it unnecessary to have a cation inside the central channel.

Now let us turn attention to the phosphate group in the acidic 5′-GMP helix. Since the phosphate group of 5′-GMP has a of 7.5, it is doubly charged at pH 8 but only singly charged at pH 5. We discovered in an earlier study [5] that two types of phosphate groups are present in the 5′-GMP helix formed at pH 8 and they are possibly bridged by a Na⁺ ion. For the 5′-GMP helix formed at pH 5, our model suggests that singly charged phosphate groups form a continuous hydrogen-bonded chain along the helical “strand” (i.e., ⋯HO--O⁻⋯HO--O⁻⋯). This type of hydrogen bond chains are commonly observed in the crystal structures of ammonium hydrogen alkylphosphates [25]. Because of this strong hydrogen bonding interaction, the P⋯P distance is significantly shorter in the acidic 5′-GMP helix, 5.2 Å, than in the neutral 5′-GMP helix (6.7 and 7.2 Å) [5]. The solid-state ³¹P NMR spectrum of acidic 5′-GMP gel exhibits a sharp peak at 1.3 ppm (vide infra), suggesting that all phosphate groups are equivalent. This is in contrast to the situation seen in the neutral 5′-GMP helix where two different phosphate groups are present with the ³¹P chemical shifts being 3.7 and 5.2 ppm [5]. Another important structural feature in the acidic 5′-GMP helix is the possible formation of a phosphate-base hydrogen bond, as first noted by Sasisekharan et al. [3]. In particular, the th phosphate group can be hydrogen-bonded to the exocyclic amino group of the th guanine base (i.e., N₂-⋯O=P) along the helical strand. In our model, the N₂⋯O(P) distance is ca. 2.82 Å.

To search for further spectroscopic evidence for the aforementioned two types of hydrogen bonding interactions involving the phosphate group (i.e., ⋯HO--O⁻⋯HO--O⁻⋯ and N₂-⋯O=P), we performed 2D ¹H → ³¹P HETCOR experiments. As seen in Figure 7(a), at a short contact time of 0.5 ms, two cross peaks were observed. The weaker cross peak with δ(¹H) of 4.1 ppm clearly arises from the short contacts between the phosphorus atom and H5′,5′′ (2.65 and 3.04 Å), as illustrated in Figure 7(b). The stronger ¹H-³¹P cross peak with δ(¹H) of 10.5 ppm is an interesting discovery, because we have already attributed, in the earlier discussion, N₁H and N₂ to this overlapping signal. Now we see that a third signal, which displays the shortest contact with the P atom, also appears in this ¹H chemical shift region. This new signal must be due to the P-OH group (the H-P distance is ca. 2.24 Å in our model); see Figure 7(b). As seen in Figure 7(a), a new cross peak corresponding to the N₂ group emerges at a longer contact time (2 ms). This is consistent with our model where the P atom is predicted to be 3.14 Å away from N₂, due to the formation of a N₂-⋯O=P hydrogen bond. This hydrogen bond further explains why the ¹H chemical shift of N₂-, ca. 8 ppm, is considerably higher than those seen in the neutral 5′-GMP helix, 5.12 and 4.29 ppm [5]. Close inspection of the acidic 5′-GMP helix suggests that the formation of this strong N₂-⋯·O=P hydrogen bond causes a tilting of the guanine base, thus making it more difficult to form a planar disc-like G₄. We postulate that the hydrogen bonding interactions between singly charged phosphate groups (⋯HO--O⁻⋯HO--O⁻⋯) and between phosphate and guanine (N₂-⋯O=P) are the driving forces for the self-assembly of 5′-GMP into a continuous helix at pH 5.

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(b)

4. Conclusion

In this work, we have obtained new structural details about the helical structure formed by 5′-GMP at pH 5. Contrary to the common assumption, we showed that this helix is composed of 5′-GMP molecules exclusively in C3′-endo sugar pucker conformation and consequently is right-handed. In addition, we found that the central channel of the helix is free of Na⁺ ions. In many aspects, this helix is drastically different from the one formed by 5′-GMP at pH 8. Remarkably, two different helices can form by the same molecule at just slightly different pH values. Of course, at pH 5 and 8, the charge state of the phosphate group would be different. The present study has provided another example where mononucleotides can self-associate into a helix in the absence of phosphodiester bonds. The solid-state NMR strategies demonstrated in this study can be applied to similar gels formed by other nucleosides and nucleotides.

Conflicts of Interest

The authors declare that there are no conflicts of interest regarding the publication of this paper.

Acknowledgments

This research was supported by the Natural Sciences and Engineering Research Council (NSERC) of Canada. The authors thank Andy Kalevar for his contributions at the early stage of this research.

Supplementary Materials

Figure S1 shows the 13C CP/MAS NMR spectrum of orthorhombic Na2(5'-GMP).7H2O.

Figure S2 shows the can1-can2 plot for RNA.

Figure S3 displays side- and top-views of the right-handed 15/4 helix formed by 5'-GMP at pH5.

Table S1 lists atomic coodinates for the right-handed 15/4 helix formed by 5'-GMP at pH5.

Supplementary Material

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Copyright © 2017 Gang Wu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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