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Cite this: Phys. Chem. Chem. Phys., 2014, 16, 7430

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A new turn in codon–anticodon selection through halogen bonds† Rajadurai Vijay Solomon, Swaminathan Angeline Vedha and Ponnambalam Venuvanalingam* The halogen bond is relatively a less characterized intermolecular interaction compared to the hydrogen bond and the structure, stability and electronic structures of halogenated base pairs, particularly at the wobble junction have been investigated using DFT. Three halogens, namely Cl, Br and I, have been

Received 20th October 2013, Accepted 29th January 2014

tested for their role in such situations with uracil as the anticodon base. Computed results reveal that

DOI: 10.1039/c3cp54442g

changes that flip some of the observed base pairs into unobserved base pairs and vice versa. NCI, NBO

when halogen atoms replace protons in the hydrogen bonding positions they induce lot of geometric and AIM analyses explain these changes at the electronic level. The new codons will have lot of impact

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in future applications, particularly in self assembly of biomaterials and t-RNA synthetic strategies.

1. Introduction Specificity and degeneracy of genetic codes are controlled by the base pair at the third position of codon–anticodon duplexes and are called wobble base pairs.1 Base pairs at this position are unique, featuring elongated distances and loose binding, enabling degeneracy. The suitable matches for the codons are chosen by the t-RNAs based on the hydrogen bonds (HB) between them.2–4 The hydrogen bonds in these base pairs and wobble base pairs have been a target for researchers over the years.5–13 The HBs were reported to break synergy with delocalization of the p-electrons and charge transfer character, which stabilizes the duplex. On the other hand, a relatively less characterized form of intermolecular interactions that attract much attention in literature is the halogen bond (XB).14–27 Due to its wide applications in molecular recognition,21,28,29 supramolecular chemistry,30–32 material science33 and biological systems,34–37 halogen bonds are of current interest.17,38–41 Though HBs are stronger than XBs, some of the stronger XBs are reported in the literature and generally the strength of the XBs lies in the range of 5 to 180 kJ mol1.28 Further the identification of shorter Br  O contacts at the Holliday junction by Hays et al.42 prompted us to ponder halogens at wobble junctions theoretically. The following questions are addressed here. What change can halogens bring about with regard to structural and energetic aspects? How different would the Theoretical & Computational Chemistry Laboratory, School of Chemistry, Bharathidasan University, Tiruchirappalli – 24, Tamil Nadu, India. E-mail: [email protected]; Fax: +91 431 2407045; Tel: +91 431 2407053 † Electronic supplementary information (ESI) available: The calculated bond parameters, deformation energies, topological properties are given. See DOI: 10.1039/c3cp54442g

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electronic environment be on replacing hydrogens for halogen, and will this change the way the anticodon is recognized by the codons? In a surge to find answers to these, we retrieved the codon– anticodon base pair geometries with uracil, cytosine, guanine & adenine as codons and uracil as an anticodon from earlier reports10,11 and replaced both the hydrogens that are involved in hydrogen bonding with halogens (Cl, Br and I). There have been number of previous studies that dealt with individual base pairs available in the literature.43–52 In order to obtain a more realistic picture, one should consider the whole protein environment. Yet, due to the high complexity and demanding computational cost, only individual base pairs have been considered here. However, this will still give useful insights which can be used to take this research to the next step. To the best of our knowledge, this is the first theoretical report on halogen bonds at wobble positions. Parker and coworkers reported that halogen bonds in DNA base pairs are found to be much weaker than hydrogen bonds in DNA base pairs35 and it is still interesting to see how they help to stabilize these wobble base pairs compared to hydrogen bonded base pairs. Their structure, stability, interaction energy, halogen bonding features and ground state stabilizing interactions are compared with the hydrogen bonded wobble base pairs and the results are presented here.

2. Computational details All calculations were carried out using the Gaussian 09W program53 and the chosen wobble base pairs and isolated bases were fully optimized at the M05-2X level,54,55 as it has been

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proved to be the most suited functional for understanding halogen bonding.56–61 The 6-31+g(d) basis set is used for all the atoms while SDD is used for iodine atoms as SDD includes relativistic contributions of the fast moving inner shell electrons.62 SDD have been used for halogen-containing molecules since they are found to be computationally more effective than all-electron basis sets.63–71 The absence of imaginary frequencies confirmed that all the optimized geometries correspond to minimum energy structures in the potential energy surface (PES). The interaction energies are calculated at the 6-311++g(d,p) level of theory through the supermolecular approach, as reported earlier.39 The Boys and Bernardi’s Counterpoise Correction Procedure is used to correct basis set superposition error (BSSE).72 A Non Covalent Interactions plot (NCI Plot)73,74 has been used to distinguish the hydrogen bonding and halogen bonding interactions, and Bader’s topological analysis is performed using AIM2000 software.75 M05-2X/6-311++g(d,p) level is used to generate the necessary wave functions for the topological analysis. Natural Bond Orbital (NBO) analysis at the M05-2X/6-31+g(d) level was used to examine stabilizing interactions in the ground state.76,77

3. Results and discussion In the present study, halogenation on the wobble base pairs with the uracil anticodon is attempted where the two hydrogens that are involved in hydrogen bonding are replaced by halogens (Cl, Br & I). Since the total number of anticodon wobble bases (AWB) is not known fully to date, the anticodon uracil is taken as the reference and its combination with four codon wobble bases (CWB) such as adenine (Ade), cytosine (Cyt), guanine (Gua) and uracil (Ura) have been chosen here. The structure, stability, strength and nature of interactions of hydrogen and halogen bonded base pairs with the uracil anticodon are discussed here. Before going into the discussion, it is important to recall the configuration of a solitary base pair10,11 which is used to predict whether a base pair will occur at the wobble position or not. The following conditions should be satisfied by the base pairs for them to be observed at the wobble position: (1) the RNN distance should not differ much from the standard Watson–Crick range (8.79–9.12 Å); (2) the dihedral angle (j) should be closer to zero; (3) the dihedral angle (a) should be less than 191; (4) divergences of up to 56.11 between the two angles (y1 & y2) are permissible. These have been reported so far in literature as decisive markers (Fig. 1). 3.1

Structural features and stability of the base pairs

The uracil anticodon base with the four major RNA bases adenine, cytosine, guanine and uracil as codon bases are considered here. The optimized geometries are given in Fig. 2 and the important bond parameters are collected in Table 1. All the halogenated wobble base pairs (WBX) show exceptional stability and well-defined dimeric structures with favourable interactions. It is well known WBHs Ura:Cyt and Ura:Ura are unobserved due to shorter RNN distances 7.13 & 7.36 Å,

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Fig. 1

Configuration markers for the Ura:Gua base pair.

respectively. The Ura:Cyt base pair is non-planar with dihedral angles (j & a) of 22.81 and 21.71, respectively, while other WBHs have a planar structure (B01). All the WBHs show two hydrogen bonds and WBXs show two halogen bonds. Surprisingly, the halogenated base pairs of the unobserved Ura:Cyt are found to have a perfect RNN distance, that can be expected of observed base pairs (i.e. the RNN distances lie over a range of 8.83 Å to 9.03 Å) and their dihedral angle is distorted remarkably (up to 20 Å) to achieve planarity upon halogen substitution. A similar situation is observed for Ura:Ura where its RNN distance shifts to 9–9.5 Å from 7.36 Å. Thus these two WBXs gain planarity and elongated RNN distances. It is interesting to note that the observed base pairs such as Ura:Ade and Ura:Gua were found to have longer RNN distances upon halogen substitution than their corresponding hydrogen bonded systems. Especially Ura:Gua(X = Cl & Br) pair show an increased RNN distance of 10.64 Å from 8.86 Å while Ura:Gua(I) elongates up to 11.02 Å and pushes the base pairs to those of the unobserved base pairs lengths. From the Table, it is clear that the computed y1 and y2 values are not altered much upon halogen substitution while the dihedral angle (a & j) approaches near-planarity upon halogenation. All these WBXs show Y  X interactions (where Y = O or N and X = Cl, Br, I), and their interatomic distances are described in the ESI† (Fig. S1–S4). Among all WBXs, the brominated base pairs are found to have shorter Y  Br distances than other halogens due to their moderate size and polarizability. However, due to the large atomic size of iodine, the iodinated WBXs show large Y  I distances. Another interesting interaction observed is the intermolecular X  X interactions and this will be discussed in detail in the AIM section. The comparable stability of mismatched RNA base pairs with that of the observed base pairs, reminds us that the

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Fig. 2

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The optimized structures of uracil anticodon wobble base pairs. Colour codes: Cl (green), Br (dark red), I (purple), C (gray), N (blue), O (red) and H (light gray).

Table 1 The selected bond parameters obtained from optimized base pairs (WBH &WBX); RNN is in (Å) & y1, y2, a and j are in degrees. Interaction energies (kcal mol1) are BSSE corrected

Base pairs

Bond parameter

X = H (WBH)

X = Cl (WBCl)

X = Br (WBBr)

X = I (WBI)

Ura:Ade

RNN y1 y2 j a Interaction energy Occurrence

8.93 124 125 0.02 0.01 13.87 Observed

10.38 118.6 119.1 7.6 3.17 4.82 Unobserved

10.59 124.4 123.7 0.01 0.01 5.39 Unobserved

10.64 113.0 114.13 0.002 0.00 8.95 Unobserved

Ura:Cyt

RNN y1 y2 j a Interaction energy Occurrence

7.13 122.19 118.04 22.8 21.49 12.41 Unobserved

8.83 125.34 113.12 3.34 1.75 4.70 Observed

8.82 127.7 110.6 0.02 0.01 7.01 Observed

9.03 130.97 106.15 4.12 1.96 14.24 Observed

Ura:Gua

RNN y1 y2 j a Interaction energy Occurrence

8.86 106.66 139.76 0.38 1.17 15.65 Observed

10.61 103.89 143.14 0.36 0.32 4.77 Unobserved

10.66 104.65 145.11 0.16 0.05 5.79 Unobserved

11.02 99.89 145.85 3.42 1.36 8.55 Unobserved

Ura:Ura

RNN y1 y2 j a Interaction energy Occurrence

7.36 94.56 138.63 0.009 0.01 11.51 Unobserved

9.09 95.66 137.95 0.01 0.00 3.82 Observed

9.13 94.76 138.38 0.012 0.00 4.57 Observed

9.54 91.20 138.95 0.002 1.36 7.03 Unobserved

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interaction energies of the base pairs alone does not determine the occurrence of a particular base pair at the wobble position.78,79 It is therefore interesting to see how halogen substitution contributes to the stability of the base pair. Therefore the BSSE corrected interaction energies are computed and have been summarized in the ESI† (Tables S1 and S2). From the Table, it can be seen that all the WBHs are more stable than the WBXs, except Ura:Cyt(I) where the iodinated Ura:Cyt base pair shows a higher interaction energy (B2 kcal mol1) than the corresponding hydrogen bonded Ura:Cyt(H) and this may be due to the shared interactions of I  N and I  O (3.299 & 2.700 Å). Further the planarity of the Ura:Cyt(I) also plays a significant role in the stabilization of the system. In the Ura:Ade system, the hydrogen bonded base pair is 3 as times stable as that of chlorine and bromine substituted base pairs. Politzer et al. and Clark et al., have rationalized the occurrence of a halogen bonding between the two electronegative atoms using the electrostatic potential map.16,17 Due to the electronic environment, size, polarizability of the halogen and the nature of the –R group which is directly attached to the halogen, a small patch of positive electrostatic potential is created on the halogen’s outermost region of electrostatic potential surface and is called a s-hole. Though the interactions in WBXs are not as stable as conventional hydrogen bonds in WBHs, the iodine-substituted WBXs show substantial stability compared to other halogenated systems (Cl & Br) and this is due to the larger size and diffusability of the iodine atom and the large s-hole it can form (Fig. 3). In the Ura:Gua case, the interaction energy lies between 4.7 to 15.65 kcal mol1 which implies that the WBH is almost twice as stable as the more promising halogenated base pair, namely Ura:Gua(I). The WBCls are the least stable base pairs and this is understandable due to small s-hole of chlorine (Fig. 3). The computed electrostatic potential values for the halogens are given in Fig. S5 (ESI†). In general these values are in agreement with the trend observed in binding energy. The deformation energy is defined as the increase in energy while the monomer undergoes distortion during complex formation, and it gives useful information on structural features.80 The computed deformation energies along with bond parameters are listed in Table S1 (ESI†) and the data show that the WBHs are noticeably more distorted upon complexation from their isolated structures than are WBXs. The formation of hydrogen and halogen bonds leads to the deformation of bases in the base pair from their isolated bases. All the N–H, N–X bond lengths that are involved in hydrogen and halogen

Fig. 3

bonding are elongated by 0.01 to 0.04 Å and due to the polarity of the iodine atoms, the N–I bonds are found to have the largest elongation in their complexes, while N–Cl bonds are affected to a lower extent. Among the halogenated Ura:Cyt & Ura:Gua systems, the iodinated systems were found to undergo more distortion compared to other halogenated systems. Meanwhile in Ura:Ade and Ura:Ura cases, the brominated systems were found to distort more than iodinated systems. The deformation energies lie in the range of 0.2 to 2.6 kcal mol1. 3.2

Noncovalent interactions

The noncovalent interactions play a decisive role in building and holding the bio-molecules together.28,34,36,81 Their importance in molecular recognition, protein folding, ligand reception and rational drug design is well known.29,82,83 Therefore, it is interesting to look into the nature of interactions by which these WBHs & WBXs are stabilized at the wobble positions. Yang and co-workers have recently introduced a noncovalent interactions plot (NCI plot) based on reduced density gradient analysis, as a possible index to classify and visualize the nature of interactions.73 S. Kozuch and J. M. Martin recently studied the characteristics of the XBs from the sign of l2, the second derivative of the electronic density in the perpendicular direction of the bond.84 Using the sign of l2, one can classify the strength of these interactions. In the NCI plot, the gradient isosurfaces are based on the sign of (l2)r. Large, negative values of l2 correspond to attractive interactions while nonbonding interactions are inferred from the large, positive values of l2. Very weak, van der Waals interactions are identified by values near zero. The reduced gradient is plotted against the sign (l2)r for all the studied base pairs and the results are depicted in Fig. 4 and Fig. S6–S9 (ESI†). Fig. 4 represents the NCI plots of Ura:Ade(H), Ura:Ade(Br) base pairs and overlaps of Ura:Ade(H) and Ura:Ade(Cl), respectively. It is interesting to note that the hydrogen bond has a large negative value whereas Ura:Ade(Br) has a lesser negative sign (l2)r. The peaks corresponding to weak inter-halogen interactions are observed near zero as indicated in Fig. 4. Furthermore, Fig. 4b demonstrates that the strength of the hydrogen bond is much stronger than that of the halogen bonds. As observed from the stability, the chlorine substitution leads to a lower stability due to weaker halogen bonding and this is clearly reflected in the Figure where the hydrogen bond peak in Ura:Ade(H) is nearly observed at 0.05 a.u. whereas the same peak is observed at 0.02 a.u. for the Ura:Ade(Cl) base pair. The shift in the peaks is indicated

The electrostatic potential maps of uracil and halogenated uracils.

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Fig. 4 NCI plots of Ura:Ade base pairs: (a) NCI Plot of Ura:Ade(H) along with its NCI analysis; (c) Ura:Ade(Br) with its NCI analysis; and (b) overlap of NCI Plots of Ura:Ade(H) and Ura:Ade(Cl). The shift in the position of the peaks clearly shows that the strength of the hydrogen bonds is stronger than that of the halogen bonds.

in Fig. 4. As we move from chlorine to iodine, the negative sign of (l2)r increases and the strength of the interactions increases more-and-more. Interestingly when comparing halogen bonds with hydrogen bonds, all the iodine bonds in WBXs, except in the case of Ura:Ade(I), are found to have stronger interaction than their corresponding hydrogen bonds in WBHs (Fig. S6–S9, ESI†). In NCI indexing, all the interactions with at least a specified fraction of the density from within a molecule are turned off, screening out only the intermolecular interactions. NCI analysis has been performed on all the optimized WBHs & WBXs, and gradient isosurfaces for noncovalent interactions of these cases are displayed in Fig. 5 where surfaces correspond to an isovalue of 0.3 a.u. and a color scale of 0.1 o r o 0.1 a.u.

The strength of the interactions are depicted by color codes; the color of the surface varies from red to blue via green where red signifies strong repulsion, green represents weak interactions, and blue symbolizes strong attraction. From the Figure, it is clear that all WBHs possess a blue isosurface and this indicates the interactions are strongly attractive. Further weak interaction between the two interacting hydrogens has been observed. Though the WBHs are strongly attractive, the regions of attraction are more confined to the axis of the hydrogen bonded atoms. Meanwhile in WBXs, the interactions are much weaker but are extended throughout the inter-base pair regions. This indicates that these halogen bonds are more electrostatically driven and are weaker than the classical hydrogen bonded WBHs.

Fig. 5 The NCI analysis of chosen wobble base pairs where the weak interactions are inferred from the green isosurface present between halogenated base pairs and strong attractive interactions are observed in hydrogen bonded cases. Colour codes: Cl (green), Br (pink), I (yellow), C (blue), N (dark blue), O (red) and H (white).

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Table 2

The computed topological properties from AIM analysis

System

Bonds

Rho in a.u.

L(r)

Ellipticity

Ura:Ade

O  H–N N–H  N N–Cl  N O  Br–N N–Br  N N–I  N O  H–N N–H  N O  Cl–N N–Cl  N O  Br–N N–Br  N O  I–N N–I  N N–H  O O  H–N N–Cl  O O  Cl–N N–Br  O O  Br–N N–I  O O  I–N N–H  O O  H–N N–Cl  O O  Cl–N N–Br  O O  Br–N N–I  O O  I–N

0.02429 0.03823 0.01748 0.00932 0.02819 0.02258 0.02923 0.02795 0.01112 0.00997 0.01507 0.01301 0.01400 0.01122 0.03070 0.03396 0.09675 0.01210 0.01560 0.01576 0.01014 0.01570 0.02759 0.02802 0.01007 0.01005 0.01482 0.01431 0.01344 0.01021

0.02019 0.02627 0.01582 0.08522 0.02215 0.01479 0.02477 0.02021 0.01145 0.00914 0.01456 0.01077 0.01137 0.08279 0.02531 0.02890 0.09976 0.01242 0.01481 0.01488 0.00802 0.01245 0.02397 0.02454 0.01040 0.01045 0.01408 0.01348 0.01064 0.00805

0.02720 0.05587 0.10830 0.01693 0.09739 0.09818 0.02630 0.05571 0.09051 0.13755 0.10892 0.14145 0.14208 0.31473 0.01766 0.02875 0.07459 0.08388 0.07342 0.09189 0.10386 0.14511 0.00977 0.01961 0.08013 0.09036 0.08935 7.54550 1.51335 1.22940

Ura:Ade(Cl) Ura:Ade(Br) Ura:Ade(I) Ura:Cyt

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Ura:Cyt(Cl) Ura:Cyt(Br) Ura:Cyt(I) Ura:Gua Ura:Gua(Cl) Ura:Gua(Br) Ura:Gua(I) Ura:Ura Ura:Ura(Cl) Ura:Ura(Br) Ura:Ura(I)

Fig. 6

3.3

Topological analysis

To gain further insight into the nature of noncovalent interactions present in these base pairs, Atoms in Molecules (AIM) theory has been used which is based on the topological properties of the electron density (r) estimated at the bond critical point (BCP) between two interacting atoms. Earlier studies have clearly pointed out that the appearance of a (3,1) BCP along the bond path confirms the presence of bonding and non bonding interactions.85–93 Bader and co-workers have proposed a set of criteria computed at the bond critical point (BCPs) to characterize the various noncovalent interactions. The strength of the bond is often measured with the help of electron density r(r) at the BCPs, whereas the Laplacian of electron density provides information about the nature of the bond. The computed topological properties have been collected in Table 2 and the molecular graphs are given in Fig. 6. From the Figure, it is clear that the hydrogen bond and halogen bond interactions are confirmed by the presence of BCPs. Each base pair was found to obey the Poincare–Hopf rule and possesses unique molecular graph feature. In Ura:Ura(X) and Ura:Cyt(X), the topologies are similar to the corresponding WBHs, in addition to the X–X interactions. Interestingly, in Ura:Cyt(X), the base pairs from one of the halides are found to be trifurcated where the halogen shares a trifurcated interaction with the N, O and X atoms and the stability of these base pairs is attributed to this. In Ura:Ade(X) lack of planarity largely deforms the topology to form only two stabilizing interactions, against three in

The molecular graphs of the uracil anticodon base pairs.

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Ura:Ade(H). While the molecular graph features only hydrogen bonds in WBHs, the WBXs exhibit Y–X  Y 0 (Y & Y 0 = O/N or N alone) as well as X  X noncovalent interactions. While the former type of interactions are conventionally called halogen bonds, the latter are called inter-halogen bonds (X  X). According to AIM, the electron density at the BCP is a measure of the strength of the bond.94 On comparison of the features of halogen bonds versus hydrogen bonds, in the WBHs, the value of r(r) at the BCP lie well within the hydrogen bonding range (0.002–0.034) with a negative L(r) value, a H(r) 4 0 and |V|/G ratio 4 1, where the potential energy term dominates in such shared interactions. This is in line with earlier reports in HBs.87,95,96 The corresponding halogen bonds have an electron density smaller than half of the hydrogen bonds’, ranging from 0.9  103 to 1.5  102. Further it is interesting to note that there is an excellent agreement with the NCI analysis and AIM results. For instance one can note that the negative sign of the l2 from the NCI analyses are in good agreement with the

Fig. 7 The computed |V|/G(r) ratio of all the N–X  Y (Y = O or N) interactions.

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strength of the interaction based on the topological properties calculated at the BCPs (Table 2 and Fig. S6–S9, ESI†). The |V|/G ratio, a sensitive index to measure the covalency97 of the halogen bonds has been plotted in Fig. 7 and this shows clearly that the halogen bonds with iodines are closer to the limits of closed shell interactions (|V|/G = 1), while in WBCl and WBBrs the |V|/G ratio of the halogen bonds (X = Cl & Br) lies in the range of 0.82 and 0.95, respectively. In the case of Ura:Ade(I), where only one halogen bond exists, the V/G ratio reaches a maximum (0.98). This shows the dominance of the potential energy at the inter-atomic surface between the base pairs with iodine bonds when compared to the other XBs. As seen from the molecular graphs of Ura:Ade(Xs), X = Cl & I have only one interaction while X = Br has two, namely O  Br–N and N–Br  N interactions (Fig. 6). The N–Br  N interaction, being shorter than the other, is found to have a higher electron density at the BCP, whereas in Ura:Cyt(X) among the two halogen bonds (N–X  O and N–X  N), N–X  O is slightly more stabilizing than the N–X  N bonds (Table 2). Topological properties at the Ura:Gua(H) and Ura:Gua(X) show that Ura:Gua(H) has two hydrogen bonds with N and O as donor and acceptor, and vice versa. Both the hydrogen bonds do exhibit equal strength in terms of the magnitude of their r(r) values; a positive H(r) value and a |V|/G ratio close to 1.02. Similarly, in Ura:Gua(X) both the interactions are much weaker than the HBs but are of equal magnitude. Furthermore, the computed topological properties clearly brings out the stable nature of hydrogen bonded WBHs over WBXs. From the molecular graphs (Fig. 6), the presence of a bond critical point between the two halogen atoms could be seen clearly and they confirm the presence of inter-halogen interactions in these halogenated base pairs; and these interactions additionally stabilize the system. Their topological properties are listed in ESI† (Table S3) and this shows that Br  Br interactions are stronger than I  I interactions and this may be due to the larger size of the iodine atoms. Further the X  X interactions are much weaker than halogen bonds observed in these modified base pairs. The halogen–halogen bond which has attracted much interaction in literature has been said to be

Fig. 8 (a) s-Hole of chlorine from the Laplacian of the rho graph of Ura:Cyt(Cl). (b) Zero-flux surfaces demarcate the inter halogen interactions along with halogen bonds.

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both stabilizing and destabilizing.98 The electron density at the X–X bond critical points indicates that these are much weaker than the corresponding N  X and O  X interactions. According to Desiraju et al.,98 X  X interactions are of two types: type 1, where y1 = y2 = 901, which are stabilizing due to increased interaction; and type 2, where y1 = 1801 and y2 = 901, which are stabilizing due to decreased repulsion; where y1 and y2 are the two Y–X–X angles. Table S4 (see ESI†) shows the computed bond angles y1 & y2 for the title cases where X–X bonds are of type 1, adding stability to the base pairs through increased Coulombic attraction. In order to gain further insights into the nature of these weak interactions, a graph of the Laplacian of rho values and zero flux surfaces has been drawn and given in Fig. 8. Fig. 8a represents the Laplacian of Table 3 The computed major second order perturbation interactions from NBO calculations

Base pairs

Filled NBO

Empty NBO

E(2)/kcal mol1

Ura:Ade

n(N2) n(O22) n(N2) n(O21) n(N2) n(O21) n(N2) n(N1) n(O20) n(N1) n(O19) n(N1) n(O19) n(N1) n(O7) n(O19) n(O8) n(O23) n(O8) n(O22) n(O8) n(O22) n(O8) n(O22) n(O7) n(O18) n(O7) n(O18) n(O7) n(O18) n(O7) n(O18)

s*(N16–H24) s*(N10–H15) s*(N15–Cl27) s*(N10–Cl26) s*(N15–Br27) s*(N10–Br26) s*(N15–I27) s*(N14–H22) s*(N8–H13) s*(N13–Cl25) s*(N8–Cl24) s*(N13–Br25) s*(N8–Br24) s*(N13–I25) s*(N13–I25) s*(N8–I24) s*(N14–H24) s*(N1–H9) s*(N13–Cl28) s*(N1–Cl27) s*(N13–Br28) s*(N1–Br27) s*(N13–I27) s*(N1–I28) s*(N11–H19) s*(N23–H24) s*(N11–Cl23) s*(N22–Cl24) s*(N11–Br24) s*(N22–Br23) s*(N11–I24) s*(N22–I23)

31.24 8.44 5.26 0.06 15.37 0.67 14.61 19.27 10.13 1.55 0.95 2.41 2.44 0.96 15.71 2.82 14.98 13.56 1.19 0.50 2.62 1.37 3.87 1.41 10.40 10.10 0.81 0.81 2.34 2.18 2.78 1.48

Ura:Ade(Cl) Ura:Ade(Br) Ura:Ade(I) Ura:Cyt Ura:Cyt(Cl) Ura:Cyt(Br) Ura:Cyt(I) Ura:Gua Ura:Gua(Cl) Ura:Gua(Br) Ura:Gua(I) Ura:Ura Ura:Ura(Cl) Ura:Ura(Br) Ura:Ura(I)

Fig. 9

the rho graph of Ura:Cyt(Cl) system, which clearly brings out the sigma hole of the chlorine atom (indicated by an arrow). Fig. 8b portrays the interhalogen interaction (Cl  Cl) where the gradient vector trajectories terminate at the boundary between the two chlorine atoms along with halogen bonds. Topological properties reveal that the strength of the X  X interactions increases in the order of Cl o I o Br. 3.4

Ground state stabilization interactions from NBO analysis

The occupied and unoccupied non-Lewis localized orbitals are often used to understand the electronic wave function on the NBO basis. The donor–acceptor natural bond orbital interactions in hydrogen and halogen bond formation are well documented in the literature and provide useful insights.16,77,99–102 Therefore NBO analysis has been performed on the optimized WBHs and WBXs at the M05-2X/6-31+g(d,p) level and the results of major second order perturbation energies are given in Table 3. The NBO analysis shows that the ground states of these wobble base pairs are mainly stabilized by two halogen bonds and one inter halogen bond. It is well known that in NBO analysis, the higher hyperconjugation interaction energies imply the stronger charge transfer from donor to acceptor. As can be seen from the Table, in all the WBHs & WBXs, a strong n - s* interaction is predominant and is due to the interaction between the lone pair on nitrogen/oxygen and the s* of N–X (X = H, Cl, Br and I). As expected, in the hydrogen bonded systems the interaction energies are much higher than those of the halogen bonded systems. The second order perturbation interaction energies vary from 0.06 kcal mol1 to 31.24 kcal mol1. Due to the higher electronegativity and smaller s-hole, the chlorinated wobble base pairs show less stabilization due to these interactions i.e. almost eight times less than that of WBHs. As one moves from Cl to I, the iodinated base pairs gain four times greater interaction energies than Cl, which may be due to a larger s-hole. The major N  X and X  X second order perturbation interactions are shown in Fig. 9. Both the lobes are present in a proper orientation and position that facilitates the stabilization in these molecules. Fig. 9a represents the two halogen bonds where the lone pair of the nitrogen is donated to the antibonding s* orbital of the N–X bond where the interacting lobes are present in such a way that they can overlap easily. It is interesting to note that a strong interaction is observed between the lone pair of nitrogen of uracil and the halogen atom in the

The major second order perturbation interaction energies obtained from NBO analysis.

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case of Ura:Ade(X), and the O  X interaction reaches a minimum or almost vanishes. This is corroborated with the AIM results where there is no bond path between the O and X. Among the halogens, bromine and iodine substituted systems show promising n - s* interactions but are very weak compared to hydrogen bonded systems. Fig. 9b illustrates the X  X interactions where the two interacting orbitals of bromine atoms resulted in n - s* interactions in addition to the two halogen bonds. Overall our results show that the predominant n - s* interactions responsible for the ground state stabilization originate from halogen bonds.

4. Conclusions In summary, halogenation of base pairs at the wobble position render suitable geometrical features to Ura:Ura and Ura:Cyt base pairs and bring them under the ‘observed’ basepairs category. Surprisingly the same halogen bonds destabilize the Ura:Gua and Ura:Ade base pairs that have so far been observed at the wobble positions. The interaction energies suggest that halogen bonds stabilize these wobble base pairs substantially, yet they are weaker than the hydrogen bonds in terms of stability. Chlorine substitution stabilizes poorly whereas bromine and iodine substitution renders much stabilization due to a larger s-hole. Halogenation on the wobble base pairs tends to change the way the base pairs interact within the complex. Halogen bonds, though weaker than the well-known hydrogen bonds, seem to twist the way the base pairs contact each other. These results raise the question, would halogenation be a new route to ‘fool’ the natural selection of base pairs? Or can this be useful in directing the tRNAs to solve the wobble puzzle in a predictive way? Will these newer rules for selection of base pairs be useful in the rational building of alternative genetic codes for man-made genes and in the assembly of biomaterials? Though nature has its own way of selecting codon pairs, with the unraveling of the complete mechanism of the steps involved in tRNA proof reading, the answers to these questions will not be too far away.

Acknowledgements R. V. S. thanks the University Grants Commission (UGC), India for financial support in the form of a Senior Research Fellowship in Maulana Azad National Fellowship (Ref. No. F.40-17(C/M)/ 2009(SA-III/MANF)). S. A. V. thanks the University Grants Commission (UGC), India and Bishop Heber College, Tiruchirappalli, India for FDP program (Ref. No. F.ETFTNBD030/FIP-XI PLAN). P. V. thanks Department of Science & Technology (DST), India for a Major Research Project (Ref. No. SB/S1/PC-52/2012). The authors thank the reviewers for their very helpful suggestions and criticisms.

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A new turn in codon-anticodon selection through halogen bonds.

The halogen bond is relatively a less characterized intermolecular interaction compared to the hydrogen bond and the structure, stability and electron...
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