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Photo-Induced Electron Transfer-Based Versatile Platform with G-quadruplex/ Hemin Complex as Quencher for Construction of DNA Logic Circuits Shuang Wang, Jian Sun, Jiahui Zhao, Shasha Lu, and Xiurong Yang Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.7b05145 • Publication Date (Web): 09 Feb 2018 Downloaded from http://pubs.acs.org on February 11, 2018

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Analytical Chemistry

Photo-Induced Electron Transfer-Based Versatile Platform with Gquadruplex/Hemin Complex as Quencher for Construction of DNA Logic Circuits Shuang Wang,†,‡ Jian Sun,† Jiahui Zhao,†,§ Shasha Lu,†,‡ and Xiurong Yang*,† †State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Changchun, Jilin 130022, China ‡ University of Science and Technology of China, Hefei, Anhui 230026, China § University of Chinese Academy of Sciences, Beijing 100039, China *Fax: +86 431 85689278. E-mail: [email protected] ABSTRACT: G-quadruplex has been developed as an innovator for analytical chemistry and biomedicine due to its vibrant binding activity, structural polymorphism and critical roles in biological regulation. Herein, a simple but versatile platform was obtained by integrating split G-quadruplex and fluorophore into a molecular beacon, where the photo-induced electron transfer could occur when the fluorophore approached the preformed G-quadruplex/hemin complexes. Such design subtly combined the G4 disruptioninduced fluorescent turn-on strategy and the photo-induced electron transfer property into one platform for constructing the logic circuits. On the basis of such universal platform, a series of binary logic gates (OR, INHIBIT, AND, and XOR), a combinatorial gate (INHIBIT-OR), and even a complex logic operation for discrimination of multiples of three from natural numbers less than ten have been successfully achieved only by employing such platform as work unit and single-strand DNAs as inputs. The set-reset function of this platform could be realized by alternatively introducing blocking and releasing strands. In addition, this platform could operate in biological matrix stably and precisely. Therefore, such universal platform lays the foundation for complicating the logic systems, realizing the biocomputing and also points out a new direction for target detection.

INTRODUCTION The bottom-up molecular logic circuits gave top-down silicon-based electronic circuits hopes due to the advantages in circumventing miniaturization limitation.1-3 In construction process of molecule circuits, DNA was widely regarded as building blocks of constructing logic gate due to its versatile features, including the parallel processing capabilities, predictability in design,4-6 and its specific recognizable ability for certain target molecules such as metal ions, small molecules, and proteins.7-12 Though a lot of logic gate systems have been put forward in virtue of preceding properties, it is still difficult to complete multifarious logic gates based on only one existing system, impeding the construction of complex logic circuits. In our opinion, the development of simple and universal logic gate platform is one of directions of settling this kind of problems. Generally, the DNA could exist in different structures, such as single strand, double strand, triplex, tetraplex and so on.13,14 Among these structures, G-quadruplex (G4), a tetraplex structure formed on guanine (G)-rich sequence, is becoming a focus of research due to its emerging roles in biological regulation, and its potential use in designing anticancer drugs and drug targets. For instance, G4 is prevalent in DNA/RNA proto-oncogenes15,16 and has close relationship with cancer and neurodegenerative disease.17-21 Additionally, G4 is also an excellent module in designing biosensors for various targets

and functional devices for nanotechnology.22-25 In fact, G4based biosensor have been frequently reported due to its multiple signal output modes (colorimetric signal based on the catalyzing activity of G4/hemin DNAzyme,26-32 increased fluorescence signal by employing its vibrant binding activities with fluorescent ligands,33,34 electrochemical and other signal changed as the distance between donor and receptor regulated by the formation of G435-37) and versatile design strategies (target-induced formation of G4 from a liberal/blocked unit28,38,39 or several split parts27,40). However, the application of G4-based DNA logic gates in computational research and analytical sciences directions was still in their infancy. Interestingly, we found that the previous reports no matter the ubiquitous G4-based biosensor or the emerging G4-based logic gates have something in common. It is the final output signals came from the G4 formation, which was classified to a G4 formation-induced turn-on strategy. In contrast, the G4 disruption-induced turn-on strategy was rarely utilized for biosensing and biocomputing. On the other hand, it has been demonstrated that there exist the photo-induced electron transfer (PET) effect between G4/hemin as a receptor and fluorophore as a donor,41,42 however, such PET effect and corresponding fluorescence response was rarely used in analytical sciences and computational research. Overall, it is highly desirable that combing the G4 disruption-induced turn-on strategy and the PET property into one platform for building the logic circuits.

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Scheme 1. Generation and suppression of PET effect between fluorophore and the G4/hemin complexes by regulation of complementary DNA.

Herein, a simple but versatile split G-quadruplex molecular beacon (SGMB) platform was successfully established by incorporating the split G4 sequence and fluorescent dye ROX into a molecular beacon, in which the split G4 stabilized by cation has the ability to bind hemin and form G4/hemin complexes that have a PET effect on the fluorescent dye ROX. The properties in this category were utilized for construction of logic circuit. In this logic circuit, the single-strand DNAs (ssDNAs) were used as inputs to disrupt the G4/hemin complexes, blocking PET effect and the fluorescence intensity varied as disruption of the G4/hemin complexes was used as output. On the basis of the same SGMB platform, a series of binary logic gates (OR, INHIBIT, AND, and XOR) and a combinatorial gate (INHIBIT–OR) had been accomplished. And then, a logic operation about discrimination of multiples of three from natural numbers less than ten was also successfully implemented. Furthermore, the SGMB platform could achieve the set-rest function by proper manipulation and operate stably in biological matrix.

EXPERIMENTAL SECTION Materials and reagents. All DNAs were designed with the help of software NUPACK, synthesized and labeled by Sangon Biotechnology Co., Ltd. (Shanghai, China). All of DNA strands were displayed in Table S1. The DNAs were dissolved in ultrapure water of 18.25 MΩ cm from Milli-Q water system, and were heated at 94°C for 5 min and then cooled down to room temperature at a rate of 6°C/min. After that, the DNA concentrations were quantified by measuring the UV absorption at 260 nm, and then stored in a refrigerator at 4°C for use. Hemin, Triton X-100 and DMSO were purchased form Sangon Biotechnology Co., Ltd. (Shanghai, China), other reagents were obtained from Sigma-Aldrich (St Louis, MO). Hemin was dissolved in 25 mM Tris-Ac buffer (200 mM Na+, 20 mM K+, 10mM Mg2+, 0.05% Triton X-100, 1% DMSO). The human blood serum was obtained from The First Hospital of Jilin University. Instrumentations. UV-Vis absorption spectra were recorded by a CARY 500 UV-Vis-NIR Varian spectrophotometer. CD spectral measurements were performed on a Jasco J-820 circular dichroism spectra polarimeter (Tokyo, Japan). Fluorescence spectra were measured on F-4600 FL spectrophotometer (Hitachi, Japan) with excitation at 588 nm and emission at 608 nm. Horiba-Jobin-Yvon Fluorolog-3 spectrofluorometer (NJ, USA) with the time-correlated single-photon counting unit was used to measure time-resolved fluorescence.

The process of logic operation. The logic gates and operation were implemented in 20 mM phosphate buffer (PB) (pH 7.4, 5 mM Mg2+) solution. The logic operation process can be divided into two parts, namely, DNA hybridization reaction and G-quadruplex-hemin interaction. In every logic gate and computing system, the SGMB and the respective inputs at a same concentration of 1 µM (The optimization of inputs strands concentration was displayed in Figure S2) were incubated at 37°C for 1.0 h to fully achieve the DNA hybridization reaction. The fluorescence measured after the DNA hybridization reaction was regarded as F0. Then the 10 µM hemin and 25 mM K+ were introduced into above mixed solution and incubated for 2 h at 37°C to ensure the fully interaction of Gquadruplex and hemin. The fluorescence measured after Gquadruplex-hemin interaction was treated as F. From above each of the samples, an amount of 100 µL was transferred to a cuvette and the resulting fluorescent signal was recorded at 608 nm for ROX. Simultaneously, we regarded single-strand DNA as the inputs, the ratio of F/F0, 0.6 was defined as output threshold value.

RESULTS AND DISCUSSION The properties of the constructed platform. The proposed SGMB platform consists of four sections: S1, S2, S3, and a fluorophore ROX modified at the 5’ end of the SGMB, in which S2 and S3 could form G4 when they were in close proximity. The as-formed G4 and S1 played the stem and loop roles in the traditional molecule beacon, respectively. (Scheme 1) The properties of such platform mainly embodies in two aspects. First, SGMB actually formed G4/hemin complexes. As the UV−vis spectra shown in Figure 1A, the shifted absorption peak of hemin from 397 nm to 404 nm suggested the formation of G4/hemin complexes, which was in accord with the reported phenomenon that an obvious hyperchromicity of the Soret band of hemin due to the binding of G4 to hemin.43,44 And the characteristic absorption peak intensity at 404 nm increased with the increase of hemin concentration (Figure S1A). Besides, the two distinct characteristic peaks of CD spectra in Figure 1B, a positive peak at 265 nm and a negative

Figure 1. UV−vis spectra (A) and fluorescence spectra (C) of SGMB (a), Unmodified SGMB (b), SGMB-S1’ (c), hemin (d), SGMB-hemin(e), SGMB-K+(f), SGMB-K+-hemin (g) and SGMB-S1’-K+-hemin (h). (B) Circular dichroism spectra of SGMB in the presence of K+, hemin and both of them, respectively. (D) Fluorescence lifetime of SGMB in absence and presence of K+ and hemin.


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Figure 2. Reconfigurations of SGMB by hybridization reaction with partial complementary stands. (A) Reconfigurations when different combinations of S1’, S2’, and S3’ were introduced into logic operation system and (B) the corresponding fluorescence intensity ratio F/F0.

peak around 240 nm, also demonstrated that the parallel Gquadruplex conformers came into being.45 While the S1’, a partially complementary strand of SGMB, disrupted the formation of G4/hemin complexes, displaying a negligible shift (Figure 1A, curve h). Second, the triggering and suppression of fluorescence quenching of SGMB were accompanied with the formation and disruption of G4/hemin complexes. As expected, >87% quenching was observed for SGMB in the presence of both hemin and K+ (Figure 1C), while SGMB with its partially complementary sequence (SGMB-S1’) did not present quenching of the fluorescence under the same condition (Figure S3). And the fluorescence intensity of ROX decreased with increasing hemin concentration (Figure S1B). In order to further confirm the reason for the fluorescence quenching, we implemented a battery of contrast experiments. For instance, the only K+ actually could lead to the formation of G4 structure (Figure 1B), but the conformational change had no influence on the fluorescence of the SGMB (Figure 1C). The complementary strand of SGMB and the strand without G4 sequence (SGMB’ and SGMB-a in Table S1) also exhibited no fluorescence quenching phenomenon (Figure S3), excluding the nonspecific binding of only hemin with the SGMB was one of possible reasons. Above results strongly suggested that the fluorescence quenching was attributed to the formation of the G4/hemin complexes, which narrowed the distance between G4/hemin and ROX. The fluorescence quenching mechanism. Typically, the main causes of fluorescence quenching might attribute to energy transfer, collisional quenching, electron transfer or the formation of non-fluorescent ground-state complexes.40 In our system, several experiments and phenomena have verified that PET results in the fluorescence quenching: (I) The 404 nm absorption peak of the G4/hemin complex (Figure 1A, curve g) did not overlap with the emission spectrum of ROX at 608 nm, excluding the fluorescence resonance energy transfer (FRET).46 (II) Hemin and K+ could not weaken the fluorescence of ROX modified at different stands that have no ability to form G4, (Figure S3) suggesting that collisional quenching of hemin for fluorescent ROX did not happen in this system.47 (III) The original absorption of ROX was retained and there was no new absorbance peak in the presence of hemin, (Figure 1A, curve g) ruling out static quenching derived from the formation of the non-fluorescent ground-state complex.48,49 (IV) The fluorescence lifetime had been shortened obviously in presence of hemin and K+. (Figure 1D) And the lifetimes of the ROX were found to decrease with increasing hemin con-

centration (Figure S5). Thus we speculated it might be the result of PET,50 where the photo-excited electrons were transferred to the G4/hemin complexes. Initially we verify that the fluorophore ROX actually have no effect on the G4 formation by using unmodified SGMB as control probe (Figure S4A). Then other common fluorophores, such as, TAMRA, CY5, and Texas Red also have a PET effect on G4/hemin complexes, and the disruption of G4 by hybridization reaction of complementary chain could suppress the fluorescent quenching. (Figure S4B) These results not only further verify the fluorescence quenching stems from the PET between fluorescent dye and G4/hemin complex, but also demonstrate the good universal applicability of the SGMB platform. The design principle of the logic circuits. In our proposal, these logic circuits mainly includes following parts: the SGMB platform as a work unit, elaborate ssDNAs as input, and the changed fluorescence signal triggered by PET effect as output. Initially, the two ends of SGMB formed G4 in presence of K+ and hemin, accompanied by the PET effect, which remarkably weaken the fluorescent emission. By contrast, the existing of partial complementary ssDNA disrupted the formation of G4/hemin conjugates through the straightforward sequence-specific hybridization, which led to the high fluorescence emission. In the construction process, the absence and presence of the ssDNAs were defined as the inputs of [0] and [1], respectively. Meanwhile, the fluorescence intensity ratio (the ratio of the fluorescence intensity in presence (F) to absence (F0) of hemin at 608 nm, F/F0) value of 0.6 was assigned as the threshold value for all the logic operation (Figure 2B). Reconfigurations of the SGMB. With such design principle in brain, our first priority is the verification for reconfiguration of the SGMB because it is a prerequisite to the construct complex DNA logic circuits. Initially, the ssDNA SGMB turned to G4 in the presence of K+ and hemin, accompanied by the fluorescence quenching derived from PET effect between the G4/hemin complexes and ROX. After different combinations of partially complementary parts of SGMB (S1’, S2’ and S3’) were introduced into the system, the G4 was disrupted with different open condition, e.g., S1’ stretched the distance between two halves of G4, while S2’ and S3’ created barriers for the G4/hemin complexes formation, retaining the fluorescence intensity of ROX (Figure 2A). These diverse reconfigurations of SGMB suggested that the platform has the potential to accomplish the construction of diverse molecular logic gates and execute complex logic operations.

Figure 3. “OR” logic gate. (A) Schematic illustration of the operational results of the “OR” gate. (B) The F/F0 608 of ROX. (C) The corresponding fluorescence image (D) The truth table of the “OR” logic gate. (E) Electronic equivalent circuitry.



Achievement of binary logic gates. The following section demonstrated that this simple but versatile SGMB platform was applied in achievement of single binary basic logic gates. For instance, a binary OR logic gate was accomplished by introducing S1’ and S3’ as Input 1 and Input 2, as well as SGMB as work unit (Figure 3). Input 1 and Input 2 bound with the loop and half of the stem respectively. Therefore, the G4 disruption-induced turn-on fluorescence signal was observed when at least one of the two inputs exists, which were satisfied with the inputs and outputs circumstances of the OR logic gate. The INHIBIT logic gate was implemented using same Input 1 and work unit in OR logic gate (Figure S6). Only in the presence of S1’, the G4 disruption could be achieved, companying a strong fluorescence emission. While other combinations of different inputs (0/0) (0/1) (1/1) showed a low fluorescence signal, because Input 2 (S1, a complementary strand of Input 1) and the completely hybrid duplex (Input 1Input 2) could not bind with SGMB and suppress the G4/hemin complexes formation. The construction of “AND” logic gate was also carried out by utilizing same work unit and different inputs elements (Figure 4). We regarded a hairpin DNA as Input 1, which blocked partially complementary strand of SGMB in its loop. The Input 2 could open the hairpin structure by toeholdmediated displacement at the 3’ end, exposing the effective sequence. Neither of the two inputs itself could suppress the formation of G4, accompanied by low fluorescence intensity. While the coexistence of the two inputs could activate the hybridization reaction with SGMB probe, resulting in a high fluorescence signal. Therefore, only inputs state (1/1) showed a true output of [1], others gave a false output of [0]. Besides, we noted that a YES logic gate was achieved when Input 2 opened Input 1 and the output of this YES gate was competent to the deconstruction work of SGMB. Hence, this function that the output of one gate in this module was employed as the input for the next gate suggested communication possibility of the system in the network gates. The “XOR” logic operation was also demonstrated as an example to show the universality of SGMB. A complementary DNA sequence S3’ was designed in the middle of Input 1 and Input 2. The SGMB probe was forced to stretch through hybridization with either Input 1 or Input 2. The two ends of the two inputs were respectively extended with two DNA sequences that could hybrid each other preferentially instead of binding to SGMB when they were present in this system

Figure 4. “AND” logic gate. (A) Schematic illustration of the operational results of the “AND” gate. (B) The F/F0 608 of ROX. (C) The corresponding fluorescence image. (D) The truth table of the “AND” logic gate. (E) Electronic equivalent circuitry.

Figure 5. “INHIBIT-OR” combination. (A) Schematic illustration of the operational results of the “INHIBIT-OR” gate. (B) The F/F0 608 of “INHIBIT-OR”. (C) The corresponding fluorescence image (D) The truth table of the “INHIBIT-OR”. (E) Electronic equivalent circuitry.

simultaneously (Figure S7). As a result, either of the two inputs could accomplish the G4 disruption, with concomitant F/F0 608 value higher than 0.6, giving the true output of [1]. While the false output signal of [0] was generated when both the two input strands are present or absent simultaneously. Overall, the successful operations of the OR, INHIBIT, AND, and XOR logic gates verified the simple but universal merit of the proposed SGMB platform, because all of these logic gates could be executed by employing the same SGMB platform as a work unit and simply substituting of the input strands in the logic system. Execution of combinatorial logic gates. Additionally, our simple but versatile platform also achieved combination of logic gates. In this combinatorial gate, the inputs used in “INHIBIT” logic gate, S1 and S1’, were integrated into “OR” logic gate by adding the third input S2’. The S1’ and S2’ could interact with the SGMB probe respectively, while the S1 exerted its function in the logic system only when the S1’ exists. As shown in Figure 5, the logic gate had an output of [1] when the inputs were (1/0/0, 0/0/1, 1/0/1, 0/1/1, 1/1/1), while other inputs (0/0/0, 0/1/0, 1/1/0) demonstrated output of [0]. In fact, the combinatorial logic gates could be understood as a process that the output of INHIBIT logic gate was used as input of OR logic gate. The successful accomplishment of three-input INHIBIT–OR combinatorial gate indicated that other combinations (e.g., INHIBIT-AND, AND-OR, XOR-INHIBIT and so on) could also be realized by designing different inputs elements without any extra complex work unit, which not only reduces significantly the difficulty and expenditure of experiments, but also demonstrates the gate networking necessity for the complex higher-order integrated circuits. Implementation of a logic operation for identification of multiples of three from natural numbers less than ten. If the construction of simple logic gates is basis and combination of logic gates is guarantee for building logic circuits, then solving practical problem by utilizing the logic circuits is the ultimate goal. Here, our proposed simple but versatile platform could get closer to this goal: identification of multiples of three from natural numbers less than ten. First, we converted every decimal digit into a four-bit binary number (Na, Nb, Nc,


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Analytical Chemistry which were shown in Figure S9. Furthermore, the stability of this SGMB probe in human blood serum was studied by monitoring the fluorescence changes of SGMB/K+/hemin complexes. The results demonstrated the quenched fluorescence showed negligible increases within eight hours.(Figure S10) These phenomena suggests that the SGMB platform might further be applied tests in vivo, such as bioimaging, intracellular drug tracing, disease diagnosis and therapy.

CONCLUSION

Figure 6. Identification of multiples of three from natural numbers less than ten. (A) Schematic illustration of the operational results of complex logic operation. (B) The F/F0 of ROX at 608 nm. (C) The corresponding fluorescence image. (D) The truth table of computational results.

Nd), then the designed four input ssDNAs were assigned to the above-mentioned four bits for computing. Among these inputs, Na and Nc could form hairpin by themselves respectively, Nb and Nd had a priority to hybridize each other at their two ends when the two strands were present simultaneously. In addition, Nb and Nd could open the Na and Nc hairpin, exposing complementary section S3’ that could bind with S3 in SGMB. The detailed computational diagram and results of the four-input binary logic operational system were displayed in Figure 6. As expected, the multiples of three (3, 6, 9) had a higher value than other natural numbers (1, 2, 4, 5, 7, 8). The successful accomplishment of this complex calculation means that the platform could achieve the identification of multiples of other numbers, because the natural numbers are determined by unit position of digit. This phenomenon also proved that the SGMB platform is integratable and universal in molecular computation. The set-reset function of SGMB. It is still a challenge for the memory function of the developed molecular computing device. Here we verified the set-reset function of such SGMB platform by employing the blocking strands (BS) and releasing strands (RS). BS and RS was derived from the two inputs of INHIBIT logic gate by adding a toehold domain at the ends of them. BS could bind SGMB and impeding the PET effect, while the fully complementary RS captured BS from partially complementary SGMB-BS hybrid by toehold-mediated strand displacement reaction. As shown in Figure S8, SGMB probe could be reversibly blocked and released when circularly introducing BS and RS, which manifest as alternative on-off switches of fluorescent signal. The good reversibility of this platform suggests its potential application in bio-computing. Construction of logic circuits in biological matrix. The biocompatibility is important for a satisfactory logic operation system, so we carried out a further inquiry for that of our designed system. Fortunately, our logic operating system represented the anti-interference and stable operation ability in a biological matrix, e.g., we executed an “OR” logic gate in 1% (v/v) human blood serum. As we all known, the human blood serum is full of polypeptide, proteins, growth factor, hormones, and so on. But the complicated components in human blood serum did not influence the computational results,

In this work, we found and established a class of simple and universal SGMB platforms including a split G4 as quencher and a fluorescent dye as reporter. It is a pretty simple platform with 31 bp ssDNA but it executed a very versatile computing function. On the basis of one of these SGMB platforms, a series of logic gates (OR, AND, INHIBIT, and XOR) were successfully constructed by employing the same SGMB work units and designing different inputs. And then we combined two binary logic gates OR and INHIBIT for achieving multilevel circuits connection, which meant that such simple and universal SGMB platform could realized the logic gates networking and computational utility. Moreover, the platform was used in solving complicated logic operation, the identification of multiples of three from the natural numbers less than ten, which facilitating the construction of complex logic circuits. More significantly, the reversibility of this platform embodied the set-reset function, suggesting its potential application in bio-computing. In addition, we executed an OR logic operation in biological matrix, suggesting this platform could resist interference and operate stably. We convince that this simple but versatile SGMB platform not only point out new direction (G4 disruption-induced turn-on strategy) for target detection and logic operation, but also has inspiring prospects in bio-computing and stimuli-responsive bioimaging by assembling the functional components (such as aptamers, pathogenic nucleic acid sequence, anti-degradation function, and so on) into it.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. All the sequences used in experiment, UV−vis absorbance and fluorescence spectra of SGMB in the presence of increased hemin, optimization of complementary strands concentration, PET effect of different DNA sequences, production and suppression of PET effect of different fluorescent dyes, fluorescence lifetime of SGMB in the presence of increased hemin, the binary “INHIBIT” logic gate, the binary “XOR” logic gate, the set-reset function of SGMB probe, “OR” logic operation in human blood serum.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] Tel.: +86 431 85262056

Author Contributions The manuscript was written through contributions of all authors.

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT



This work was financially supported by the National Natural Science Foundation of China (No. 21435005, 21627808, 21605139) and Key Research Program of Frontier Sciences, CAS (QYZDYSSW-SLH019)

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