DNA-Enforced Conformational Restriction of an Atropisomer

Article pubs.acs.org/JPCC DNA-Enforced Conformational Restriction of an Atropisomer Rijo T. Cheriya,† Jimmy Joy,† Shinaj K. Rajagopal, Kalaivanan Nagarajan, and Mahesh Hariharan* School of Chemistry, Indian Institute of Science Education and Research Thiruvananthapuram, CET Campus, Sreekaryam, Thiruvananthapuram, Kerala, India 695 016 S Supporting Information * ABSTRACT: We report the conformational restriction of a freely rotating biaryl derivative resulting in strong exciton coupled circular dichroism between the two nondegenerate fragments of the dyad NP only in the presence of DNA. The napthalenimide−perylenimide dyad NP, an extended 1,1′-binaphthalene derivative, has a rotational barrier of 100 kJ/mol, leading to fast racemization. While end-stacking with a DNA hairpin, NP exhibits a significantly high rotational barrier, an additional 91 kJ/mol, resulting in atroposelective preference. Such reversible conformational constraints using biotemplates show huge potential toward conformational analysis, dynamic kinetic resolution, and asymmetric synthesis. The present work focuses on conformational analysis of a freely rotating biaryl derivative using a combination of techniques such as temperature-dependent UV−vis, circular dichroism, steady-state and time-resolved fluorescence spectroscopy, and molecular dynamics simulation. no circular dichroism signal. The syn pathway experiences close contact between the 2, 2′ and 8, 8′ hydrogen atoms while the anti pathway offers lower steric hindrance due to close contact between the 2,8′ and 2′,8 hydrogen atoms (Figure S1, Supporting Information). In contrast, when covalently attached to the DNA hairpin, NP exhibits strong exciton coupled circular dichroism signals in the chromophoric regions corresponding to both napthalenimide and perylenimide. This is possible only if the racemic NP, which shows no exciton coupled circular dichroism, is conformationally locked by the DNA, offering preferential chirality from the regular B-form geometry. Molecular dynamics simulation of NP, in the context of the DNA, showed that NP exhibits a distinct dihedral angle (60°) between the napthalenimide and perylenimide via end-stacking between the perylenimide and the adjacent base pair of the DNA. This end-stacking interaction facilitated by hydrophobic interactions prevents the racemisation of the dyad NP in the context of the end-capped DNA. Such atroposelective biaryl precursors, conformationally constrained by the DNA, have prospective applications in the area of conformational analysis and atroposelective synthesis.24 INTRODUCTION Life forms perform marvelous acts of chiral recognition orchestrating the dexterity of biological molecules at the cellular level.1 Bio-inspired chiral recognition is an emerging area that utilizes chiral templates2−4 such as peptides,5,6 nucleic acids,7,8 carbohydrates,9 and cholic acids.10 Recently, hydrogenbonded interactions between a biaryl substrate and a tripeptide (chiral auxiliary) was effectively employed to conformationally restrict the precursor that lead to an atropisomeric excess.5 Extensive efforts have also been directed at the resolution of the atropisomers of unsubtituted racemic 1,1′-binaphthalene.11 Employing hydrophobic interactions to induce the resolution of racemic rotamers could have promising applications in conformational analysis. Using nucleic acids to control the conformation of biomacromolecules has been elucidated,12,13 but chirally biasing racemic small molecules through noncovalent hydrophobic interactions with nucleic acids14−17 demands further attention. To our best knowledge, the present work represents the first example of a DNA-enforced conformational restriction of a freely rotating biaryl derivative through hydrophobic interactions, resulting in the conformational preference of an enantiomer. We report the synthesis, characterization, and conformational analysis of a napthalenimide−perylenimide (NP) dyad endcapped hairpin DNA (Figure 1). Exciton coupled circular dichroism18−22 is employed to monitor the coupling between the two chromophoric transition dipoles corresponding to those of napthalenimide and perylenimide. By virtue of the lower steric hindrance through the anti pathway (100 kJ/ mol),23 the binaphthalene derivative NP having nondegenerate transition dipoles undergoes racemization and hence displays ■ © 2012 American Chemical Society RESULTS AND DISCUSSION Synthesis and Characterization. The dyad NP was synthesized through Stille coupling between the tributyltin derivative of N-hydroxypropylnaphthalenimide and bromoperylenimide (Figure 1A and Scheme S1), as reported earlier.25 ■ Received: August 20, 2012 Revised: September 22, 2012 Published: September 26, 2012 22631 dx.doi.org/10.1021/jp308260a | J. Phys. Chem. C 2012, 116, 22631−22636 The Journal of Physical Chemistry C Article Figure 1. (A) Naphthalenimide−perylenimide dyad (NP) and (B) NP end-capped hairpin DNA ODN1 and model hairpin DNA ODN2. (C) X-ray crystal structure of racemic dyad NP. Figure 2. Lowest energy structure of (A) NP end-stacked and (B) NP unstacked DNA conjugate ODN1 (hairpin loop is omitted during simulation). (C) Activation energy diagram for the racemisation of atropisomers in the absence (black) and presence (red) of DNA. (D) Frequency distribution of dihedral angle between molecular planes of naphthalenimide and perylenimide in end-stacked (green) and unstacked (red) conformer of ODN1; inset of (D) shows the instantaneous values of the dihedral angle between chromophoric units in the dyad NP incorporated in the ODN1 as monitored by MD simulations for end-stacked (green) and unstacked (red) conformer. Activation energy for the interconversion of (M)-NP and (P)-NP, in the context of DNA, is determined from the difference in single point energy of respective atropisomeric NP in the end-stacked and unstacked form of DNA. fluorescence emission centered around 575 nm, corresponding to the perylenimide unit (Figure S2B). In order to study the effects of DNA on the conformation of the dyad NP, we incorporated NP as an end-cap to a short DNA hairpin. Incorporation of only a single NP per DNA hairpin is vital to avoid coupling between the degenerate transition dipoles, i.e., naphthalenimide−naphthalenimide or perylenimide−perylenimide, which is possible in a solution of noncovalently associated multiple chromophores and DNA.27 The NP end-capped hairpin oligonucleotide ODN1 and the model hairpin ODN2 (Figure 1B) were synthesized using the standard phosphoramidite method, purified through reverse phase HPLC (Figure S3), and characterized by MALDI-TOF mass spectrometry (Figure S4 and Table S1). Thermal The X-ray crystal structure of the dyad NP clearly shows the near-orthogonal arrangement (dihedral angle of 75°) of the chromophoric units having both the chiral forms in the unit cell (Figure 1C). The absorption spectrum of dyad NP is the sum of the absorption spectra of naphthalenimide centered at 340 nm and perylenimide centered at 480 nm, indicating that NP behaves as two separate chromophores though connected by a single covalent bond (Figure S2A).25 We observed no circular dichroism (CD) signal corresponding to either the naphthalenimide or the perylenimide unit of the dyad NP for a solution in DMSO, indicating the presence of equal amounts of mutually enantiomeric atropisomers26 of the NP dyad. Upon excitation at 475 nm, the dyad NP in DMSO exhibited 22632 dx.doi.org/10.1021/jp308260a | J. Phys. Chem. C 2012, 116, 22631−22636 The Journal of Physical Chemistry C Article mide moiety and the adjacent base pair is reversible in nature by virtue of the reversibility of the noncovalent hydrophobic interactions unlike the irreversible effect of substitution at the 2,2′-positions of 1,1′-binaphthalene. In contrast, MC conformational search for the (P)-atropisomer of the NP end-stacked and NP unstacked ODN1 exhibited a difference in single point energy (3933 kJ/mol; Figure S6), favoring NP unstacked conformation. Such destabilization in the case of (P)atropisomer containing ODN1 could be attributed to inefficient hydrophobic interactions between the end-stacked dyad NP and the adjacent base pair generating increased strain on the propyl linker (Figure S6A). UV−vis and CD Spectroscopy. Figure 3 shows temperature-dependent UV/vis and CD spectra of NP end-capped denaturation temperature of ODN1 determined by monitoring UV−vis absorption at 260 nm (Tm = 40.1 °C) in 10 mM phosphate buffer (pH 7.2) containing 100 mM sodium chloride is higher (ΔTm = 1.3 °C) than the model hairpin DNA ODN2 (Tm = 38.8 °C; Figure S5 and Table S2). The marginal increase in the thermal stability of ODN1 when compared to ODN2 could be attributed to the enthalpy−entropy compensation arising from the association of the dyad NP with the adjacent base pair.28,29 The observed thermodynamic stability of the ODN1 is in good agreement with chromophore end-capped hairpin oligonucleotides reported earlier.21 The orthogonal arrangement of the chromophoric units present in NP in combination with the short linker length (n-propyl) prevents the dyad from intercalating between the base pairs of DNA.30 Simulation. We performed Monte Carlo conformational search (MC)31 and molecular dynamics (MD) to understand the conformation of the dyad NP when 5′-end-capped on the DNA hairpin. Monte Carlo conformational search and molecular dynamics were carried out through simulations performed using the Schrödinger suite of programs with the MacroModel v9.9 module, based on the AMBER force field. The initial structures for both MC and MD were constructed from B-form duplex DNA, and the duplex alone was constrained during all the simulations. MD simulations were done over a time scale of 20 ns, sampling 1000 structures at 300 K. Dynamics were simulated using time steps of 1.5 fs and an equilibration time 1.0 ps. MC conformational search on (M)atropisomer of NP end-stacked (Figure 2A) and NP unstacked (Figure 2B) DNA hairpins showed a significant difference in the single point energy (91 kJ/mol; Figure 2C) favoring the end-stacked conformer. Single point energies were calculated using the Current Energy option in Macromodel (Force field: AMBER; solvent: Water, Electrostatic treatment: Force field defined) on the optimized oligonucleotide structures obtained via the MC conformational search. The energy profile for the interconversion of the (M)- and (P)-isomers of NP in the absence of the DNA (black trace) was taken to be similar to that of binaphthalene reported previously23 and hence has a similar activation energy for rotation, i.e., 100 kJ/mol. The energy profile for NP in the presence of the DNA was obtained from the single-point energy calculations performed on the optimized structures of both the (M)- and (P)-isomers of NP end-stacked on the hairpin DNA. The (M)-NP end-stacked DNA was found to be stabilized by 91 kJ/mol when compared to the NP unstacked DNA while (P)-NP end-stacked DNA was destabilized by 3933 kJ/mol. Thus, in the presence of DNA, (M)-NP is stabilized by 91 kJ/mol (Figure 2C; minima on left side of the barrier) and (P)-NP is destabilized by 3933 kJ/mol (Figure 2C; minima on right side of the barrier). MD simulations on ODN1 showed that the dyad NP remains end-stacked throughout the 20 ns simulation time scale at 300 K. Interestingly, the dihedral angle between the two planes of the dyad NP is found to be 60 ± 5° (Figure 2D) when endstacked on the DNA (sampled over 1000 structures), while in the unstacked conformer of ODN1, NP behaves similar to the free dyad in solution with large fluctuations in the dihedral angle, i.e., 81 ± 20°. The observed increase in barrier to rotation in NP when end-stacked in DNA (191 kJ/mol) due to strong hydrophobic interaction between perylenimide moiety and the adjacent base pair32 inhibits racemization, similar to the effect of 2,2′-disubsitution in 1,1′-binaphthalene (150−170 kJ/ mol).23 It should be noted that the additional 91 kJ/mol barrier arising from hydrophobic interactions between the peryleni- Figure 3. Temperature-dependent (A) UV−vis and (B) circular dichroism spectra; arrows indicate the increase in temperature from 0 to 50 °C. (C) Thermal denaturation curves of ODN1 in 10 mM phosphate buffer (pH 7.2) containing 100 mM NaCl. hairpin DNA ODN1 in 10 mM phosphate buffer (pH 7.2) containing 100 mM NaCl. With increasing temperature, the UV−vis absorption centered at 525 nm corresponding to perylenimide moiety exhibited a significant hypsochromic shift (10 nm; Figure 3A), resulting in a UV−vis spectrum similar to that of NP (Figure S2A). We also observed a strong exciton coupled circular dichroism at the perylenimide and naphthalenimide regions (Figure 3B). A negatively bisignated CD (−576 nm; +510 nm) with a zero crossing at 540 nm corresponds to perylenimide unit is observed, consistent with 22633 dx.doi.org/10.1021/jp308260a | J. Phys. Chem. C 2012, 116, 22631−22636 The Journal of Physical Chemistry C Article Figure 4. (A) Temperature-dependent fluorescence emission spectra of ODN1 in 10 mM phosphate buffer (pH 7.2) containing 100 mM NaCl; inset shows area under the emission spectra vs temperature. Excitation wavelength: 475 nm. (B) fluorescence anisotropy decay of ODN1 in 10 mM phosphate buffer (pH 7.2) containing 100 mM NaCl recorded at 0 °C in comparison with the model derivative NP in DMSO. distance separation. Thus, the exciton coupled CD signal at the naphthalenimide/perylenimide regions arises from the interaction of their respective dipoles when restricted in a favorable orientation by the DNA, as opposed to the racemic dyad NP in DMSO. Fluorescence Spectroscopy. We also carried out fluorescence emission studies of NP and ODN1 excited at 475 nm, corresponding to perylenimide unit (Table S3) at 25 °C. A significant decrease in fluorescence quantum yield is observed for ODN1 (Φem = 0.12) in 10 mM phosphate buffer (pH 7.2) containing 100 mM sodium chloride when compared to the model dyad NP (Φem = 0.7). The decrease in fluorescence quantum yield of NP in the context of DNA is indicative of strong interaction between the chromophore NP and the DNA. Time-resolved fluorescence studies of ODN1 at 25 °C (Figure S7 and Table S3) exhibited a biexponential decay with the lifetimes of 1.08 ns (30%) and 3.29 ns (70%), whereas the model derivative NP in DMSO exhibited a monoexponential decay with a lifetime of 3.79 ns. The reduced lifetime of NP (1.08 ns) in the context of DNA clearly indicates the end-stacking interaction between perylenimide and adjacent base pair, whereas the long-lived (3.29 ns) component arises from NP when it is unstacked from the hairpin DNA in ODN1, which is consistent with the MC conformational analysis. Temperature-dependent fluorescence spectra of NP endcapped ODN1 in10 mM phosphate buffer (pH 7.2) containing 100 mM sodium chloride when excited at 475 nm are shown in Figure 4A. A sigmoidal increase in the fluorescence intensity corresponding to perylenimide unit saturating at 40 °C with increase in temperature is observed (inset of Figure 4A). This temperature (40 °C) could be assigned to complete dissociation of the end-stacked NP from the hairpin structure, which occurs at a similar temperature when compared to the thermal denaturation temperature of the DNA (40.1 °C), as expected. Moreover, the temperature at which complete disappearance of exciton coupled CD signal (40 °C) is also in good agreement with the fluorescence data. Anisotropy Measurement. Fluorescence anisotropy decay of NP end-capped DNA ODN1 in comparison with the model derivative NP in DMSO is shown in Figure 4B. The anisotropy of ODN1 in 10 mM phosphate buffer (pH 7.2) containing 100 mM NaCl decays monoexponentially with a lifetime of 2.91 ns and an initial anisotropy of 0.34 (r0). While the model derivative NP in DMSO showed a reduced anisotropy lifetime that of maximum in the UV−vis spectrum of NP. While a zero crossing at 387 nm which is red-shifted with respect to the absorption maximum (345 nm) and a negatively bisignated CD (−416 nm; +351 nm) is assigned to the naphthalenimide unit. The observed bisignated CD signal at the chromophoric regions is the consequence of nondegenerate exciton coupling between the napthalenimide and the perylenimide units.33 The red-shift in the zero crossing of the bisignated curve arising from the coupling of nondegenerate dipoles is consistent with exciton coupling in photosynthetic antenna, as reported earlier.34 In addition, we observed a strong positively bisignated CD signal (+276 nm; −247 nm) corresponding to regular Bform DNA. Similar observations were made in hairpin DNA having CG base pair at different distances from NP and also in the absence of the CG base pair (data not shown). CD melting curves exhibited a complete loss of exciton coupled signal corresponding to naphthalenimide and perylenimide regions with a melting temperature of 40 °C (Figure 3C). A long halflife of >72 h at 40 °C was observed using exciton coupled circular dichroism data for the racemization of dyad NP while end-capped to the DNA, as compared to the reported half-life of 14.5 min for 1,1′-binaphthalene under similar conditions.23 Typically, association of an achiral chromophore to the chiral DNA results in a weak induced circular dichroism (ICD) signal at the chromophoric region, with no bisignation. In contrast, a short separation distance between two or more chromophore units and the conformational locking of the chromophores (e.g., when bound to DNA) can lead to exciton coupled circular dichroism. The strength of exciton coupling is maximum when the projection angles of the interacting transition dipole moments are any other than 0° or 180°, with a maximum occurring at 70°.18 The nondegenerate exciton coupling between naphthalenimide or perylenimide and the DNA bases is extremely weak.35 Even though the transition energy separation between naphthalenimide unit and perylenimide (180 nm) is twice as that of DNA base pair and naphthalenimide unit (90 nm), the close proximity between naphthalenimide and perylenimide unit compensates, leading to strong exciton coupling, in contrast to the DNA base pair which is spatially separated from the chromophoric unit. Exciton coupling between perylenimide and the adjacent DNA base pair could be ruled out because of two following reasons: (i) the large separation in the transition energy between the DNA bases and perylenimide unit (270 nm) and (ii) the 22634 dx.doi.org/10.1021/jp308260a | J. Phys. Chem. C 2012, 116, 22631−22636 The Journal of Physical Chemistry C Article of 1.28 ns (r0 = 0.37). The observed anisotropy lifetime of ODN1 is structurally consistent with the chromophore being attached to the terminus of the hairpin DNA. The 3 ns time constant is in good agreement with the reorientation time scales of oligonucleotides with similar sizes36 and clearly rules out the possibility of assembly of the DNA conjugates. The possibility of such supramolecular aggregation of the oligonucleotides is ruled out even at a higher NaCl concentration, as reported earlier.35,37 The CD spectrum recorded for ODN1 in 10 mM phosphate buffer (pH 7.2) containing 1 M NaCl (Figure S8) is identical to that of the CD spectrum recorded at low salt conditions. The absence of tri/ tetra-signations in the CD signal clearly confirms the absence of dimerization of NP fragment in ODN1 under given conditions. The two nondegenerate chromophoric dipoles in NP, i.e., naphthalenimide and perylenimide, connected across the single bond can rotate freely through the anti pathway (Figure S1) with a racemization half-life of 14.5 min at 50 °C and rotational barrier of 100 kJ/mol (ΔG⧧), similar to that of 1,1′binaphthalene reported by Havlas and co-workers.23 While NP in the presence of DNA, i.e. as observed in ODN1 where it end-stacks with the base pairs, exhibits much longer half-life of racemization at 40 °C (>72 h) which arises from hydrophobic interactions between perylenimide and the adjacent base pair that leads to the atroposelective conformational locking of NP in agreement with molecular modeling. The preferential sense of axial chirality could be imparted from the difference in the extent of interaction between (M) and (P) atropisomer of the dyad NP with the adjacent base pair. At elevated temperature (>40 °C), absence of exciton coupled CD signal indicates the racemization of NP in the context of ODN1. Interestingly, ODN1 regained the exciton coupled negatively bisignated CD signal corresponding to the (M)-atropisomer of NP when temperature is lowered to 0 °C. The formation of (M)atropisomer is confirmed through simulated CD spectra of (P) and (M) isomers obtained using the time-dependent density functional theory (TD-DFT) method (Figure 5).38 Thus, the dyad NP in the context of DNA could be racemized at higher temperature and spontaneously resolved to the (M)-atropisomer at lower temperature in a reversible manner without hysteresis. CONCLUSIONS In summary, we have demonstrated the ability of DNA to bias a racemic biaryl derivative toward a unique atropisomer through hydrophobic interactions between the perylenimide fragment of the dyad and the adjacent base pair (DNA striction). Unlike the irreversible effect of substitution at the 2,2′-positions of 1,1′binaphthalene, the strong noncovalent hydrophobic interactions between perylenimide moiety and the adjacent base pair inhibits racemization of the atropisomeric dyad reversibly, thus allowing the dyad to be racemized and resolved. Such preorganization of achiral molecules into chiral transient species using DNA can have potential application in the area of conformational analysis, dynamic kinetic resolution, and atroposelective synthesis. ■ ■ ASSOCIATED CONTENT S Supporting Information * Synthesis, characterization, thermodynamic, photophysical, and chiroptical data of NP end-capped hairpin conjugate ODN1 and model DNA hairpin ODN2. This material is available free of charge via the Internet at http://pubs.acs.org. ■ AUTHOR INFORMATION Corresponding Author *E-mail [email protected]. Author Contributions † These authors contributed equally to the manuscript. Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS The authors thank Prof. Fred Lewis, Northwestern University, and Dr. Anil Shaji, IISER-TVM, for helpful discussions. They also thank Prof. E. D. Jemmis for extending the computational facility and Schrödinger Suite. M.H. acknowledges the Science and Engineering Research Board (SERB) for the support of this work, SERB/F/0962. ■ ■ REFERENCES (1) Lehninger, A.; Nelson, D.; Cox, M. Lehninger Principles of Biochemistry; W.H. Freeman: New York, 2008. (2) Demers-Carpentier, V.; Goubert, G.; Masini, F.; Lafleur-Lambert, R.; Dong, Y.; Lavoie, S. p.; Mahieu, G.; Boukouvalas, J.; Gao, H.; Rasmussen, A. M. H.; et al. Science 2011, 334, 776−780. (3) Wang, J.; Feringa, B. L. Science 2011, 331, 1429−1432. (4) Rauniyar, V.; Lackner, A. D.; Hamilton, G. L.; Toste, F. D. Science 2011, 334, 1681−1684. (5) Gustafson, J. L.; Lim, D.; Miller, S. J. Science 2010, 328, 1251− 1255. (6) Kumar, C. V.; Buranaprapuk, A.; Sze, H. 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