Sulfur as an Acceptor to Bromine in Biomolecular Halogen Bonds

Letter pubs.acs.org/JPCL

Sulfur as an Acceptor to Bromine in Biomolecular Halogen Bonds Melissa Coates Ford, Matthew Saxton, and P. Shing Ho* Department of Biochemistry & Molecular Biology, Colorado State University, 1870 Campus Delivery, Fort Collins, Colorado 80523-1870, United States S Supporting Information *

ABSTRACT: The halogen bond (X-bond) has become an important design element in chemistry, including medicinal chemistry and biomolecular engineering. Although oxygen is the most prevalent and best characterized X-bond acceptor in biomolecules, the interaction is seen with nitrogen, sulfur, and aromatic systems as well. In this study, we characterize the structure and thermodynamics of a Br···S X-bond between a 5bromouracil base and a phosphorothioate in a model DNA junction. The single-crystal structure of the junction shows the geometry of the Br···S to be variable, while calorimetric studies show that the anionic S acceptor is comparable to or slightly more stable than the analogous O acceptor, with a −3.5 kcal/mol difference in ΔΔH25°C and −0.4 kcal/mol ΔΔG25°C (including an entropic penalty ΔΔS25°C of −10 cal/(mol K)). Thus sulfur is shown to be a favorable acceptor for bromine X-bonds, extending the application of this interaction for the design of inhibitors and biological materials.

I

The most common X-bond acceptor in biomolecules is the carbonyl oxygen of the peptide bond, primarily because of its prevalence in proteins,4,27,28 although the amino acid side chains collectively are nearly equivalent in their representation.8,29 The sulfur-containing amino acids, particularly Cys, are underrepresented as X-bond acceptors,8,29 but Met has potential as a target for inhibitor design.14 Experimental and computational studies on small-molecule systems show sulfur as similar to or slightly more favorable than oxygen as an Xbond acceptor30,31 with geometries that deviate significantly from linearity.30,32 A study of iodobenzenes bound in cavities engineered into T4 lysozyme, however, indicated that the I···S or I···Se X-bond was not significantly different in energy compared with standard van der Waals interactions.33 Thus it is not clear how strong S would be as an X-bond acceptor in a biomolecular system. Our lab has developed a DNA Holliday junction model to study X-bonds in a biological context,10,34,35 in which a halogenated uracil (XU in a decanucleotide sequence d(CCGGTA6XU7CCGG), Figure 2) is placed at a nucleotide position to form an X-bond. This X-bond replaces a stabilizing H-bond to the phosphate backbone of nucleotide A6 at the sharp Uturn of the crossing strand of the four-stranded junction in the stacked-X geometry. The single-crystal structures of these constructs reveal the detailed geometries, while melting studies through differential scanning calorimetry (DSC) measures the energetics of the molecular interaction in solution. Finally, quantum-mechanical (QM) analyses on models of the interacting groups within the DNA junction help bridge the

nterest in the halogen bond as a tool in the biological sciences1−3 has grown since its rediscovery as a stabilizing interaction that both conveys specificity in inhibitor recognition4−9 and controls the structure and stability of nucleic acids10 and proteins.11 The term “halogen bond”12 (X-bond) has been adopted to reflect its analogous behavior to the better known hydrogen bond (H-bond). In particular, any H-bond acceptor can potentially serve as an X-bond acceptor.13 Most recent studies have focused on oxygen, nitrogen, and πelectron systems as X-bond acceptors because of their prevalence in biomolecules.8 Sulfur is also commonly seen as an acceptor4,8 and is gaining attention as a potential X-bond target in drug design,14 but there is currently very little understanding of its X-bonding potential in a biological system. Here we adopt a DNA Holliday junction as a model to determine the structure-energy relationship of Br···S X-bonds and find that an anionic sulfur is comparable to or slightly stronger as an X-bond acceptor relative to oxygen, even in geometries that are not as ideal for this type of interaction. The X-bond, similar to the H-bond, is considered to be primarily an electrostatically driven interaction,15−17 although charge transfer, dispersion, and polarization contribute significantly.18−20 In the electrostatic σ-hole model, the Xbond donor is an electropositive crown created at the tip of a halogen substituent as a consequence of depletion of electron density opposite a covalent σ-bond (e.g., a CX bond, Figure 1).15 The resulting “σ-hole” interaction with an electron-rich acceptor is shorter than the sum of the van der Waals radii (∑rvdW) of the respective atoms, with a linear approach of the acceptor to the halogen (θ1 angle). The σ-hole is most pronounced with the heavier halogens (Cl < Br < I; F is not a significant X-bond donor in biology) and is accentuated by electron-withdrawing groups. © XXXX American Chemical Society

Received: July 5, 2017 Accepted: August 10, 2017 Published: August 10, 2017 4246

DOI: 10.1021/acs.jpclett.7b01725 J. Phys. Chem. Lett. 2017, 8, 4246−4252

Letter

The Journal of Physical Chemistry Letters

Figure 2. X-bonding interactions with oxygen as the acceptor at the crossover in a DNA junction. The overall junction (PDB code 2ORG10) is shown, with the inset depicting the 5-bromouracil base at Br U7 interacting with phosphate oxygen pA6. Replacement of an oxygen with a sulfur in this phosphate group, as a phosphorothioate in the junction (ps-J), creates a prochiral center at the phosphorus, defining the two prochiral configurations of the sulfur (labeled pro-Rp and pro-Rs), either of which could form a Br···S X-bond.

Figure 1. X-bond. (a) σ-Hole model for X-bonding.15 As a halogen becomes covalently bonded, for example, to a carbon, the pz-orbital of the halogen is depopulated when the valence electron is subsumed by the resulting σ-bond molecular orbital, creating a “σ-hole”. This hole accounts for the electropositive charge and polar flattening in the direction opposite the σ-bond. The electrons that remain in the perpendicular px,y-orbitals create an anisotropic charge distribution across the halogen’s surface. (b) Comparison of H- and X-bond donors and acceptors in biological systems and relationships between the two. Because both H- and X-bonds are primarily electrostatically driven interactions, they share a common set of electron-rich acceptors. When a H- and X-bond share a common acceptor, such as the carbonyl oxygen of the peptide backbone in a protein, the interactions are known to be orthogonally related (in terms of both geometry and their energy independence).21 The anisotropic charge distribution results in halogens being amphoteric, allowing them to serve simultaneously as X-bond donors and H-bond acceptors.13,22−25 Adapted with permission from refs 4 and 26. © 2004 National Academy of Sciences; © 2016 American Chemical Society.

Unlike previous work, all four strands of each construct are identical, forcing an X-bond to form in all structures instead of having one compete against the other. We will, however, use the previously published structure with a Br···O X-bond (PDB code 2ORG10) as a model for the interactions in p-J. The overall structure of the ps-J is that of the four-stranded DNA junction, similar to the stacked-X junctions seen previously (Figure 3a).10,51 The overall junction geometries (Jtwist, which relates the rotational angle between the stacked arms along their helical axes, and Jroll, which relates the stacked arms perpendicular to the helix axes) indicate that the global geometries of the two conformations are very similar (Table 1). The primary difference is that the stacked duplex arms of the sulfur containing junction are related by a much shallower angle (Jtwist ≈ 30° compared with ≥40° in all previous structures,36−40 including those with X-bonds51), making it a more planar junction structure. During refinement of the structure, it was clear that the sulfur of the phosphorothioate at A6 was the pro-Rp enantiomer at the core of the junction and positioned close to the bromine on BrU7. Careful analysis of the residual electron densities in the Fo-Fc difference map (Figure 3b), however, indicated that the ps-linkage assumed two conformations, labeled here as conformer A (ps-JA, with 52% occupancy) and conformer B (ps-JB, with 48% occupancy), and was subsequently confirmed by reductions in the Rwork and Rfree values when both conformations were included in the final model (with Rwork dropping from 22.5 to 21.8% and Rfree dropping from 27.8 to 27.6% with the addition of two conformations). Finally, the presence of these two conformations was further supported by analysis of the structural B-

structural details of the crystals with the associated stabilizing energies in solution. We apply this same DNA junction system here to determine the structure−energy relationship of a Br···S X-bond by introducing a phosphorothioate (ps) in place of the standard phosphate (p) linkage between A6 and XU7 (where X = Br), thereby allowing us for the first time to directly compare sulfur to oxygen as biomolecular X-bond acceptors. The goals of the current studies are to determine the structure−energy relationship of sulfur as an X-bond acceptor and to compare against the more prevalent oxygen acceptor in a biomolecular system. From our previous studies,10,51 bromine was found to be the overall most stabilizing X-bond donor in our model DNA junction to an anionic oxygen acceptor. We have thus designed two DNA junction constructs, the first in which the X-bond acceptor is the anionic oxygen of a standard phosphate (p) diester linkage between T5 and A6 in the sequence (CCGGT5pA6BrUCCGG, called p-J), and the second is the sulfur of a phosphorothioate (ps) in the sequence (CCGGT5psA6BrUCCGG, called ps-J). 4247


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The local structures of the T5 and the A6 nucleotides at the point of junction crossover differed among the two Br···S conformers. In particular, the base pair from T5 to its complementary A6 base is slightly stretched in ps-JA compared with ps-JB (Table 1). A more detailed analysis showed the sulfur of ps-JA approaches the Br of BrU7 at a closer distance (rBr···(S/O)) and more linearly (θ1) than that of ps-JB (Figure 3c,d, Table 2). It is clear from the geometries that ps-JA forms an X-bond, which pulls T5 base slightly away from the A6 base on the complementary strand. Table 2. Geometries of the Br···(O/S) X-bond phosphate pJ Junction Construct and the Two Conformers of the Phosphorothioate (ps-JA and ps-JB) Structures, Including the Distance between Interacting Atoms (rBr···(O/S)), the Distance as a Percentage of the Sum of the Respective van der Waals Radii (%∑rvdW), and the Angle of Approach of the Acceptor to the Br−C Bond (θ1)

Figure 3. X-ray crystal structure of phosphorothioate DNA junction (ps-J). (a) Phosphorothioate DNA junction (ps-J) crystallizes as a stacked-X four-stranded junction. The junction was seen to adopt two conformations (ps-JA in blue and ps-JB in orange). (b) Electron density map at the junction crossover. The 2Fo-Fc electron density map calculated at the 1σ level (blue wire) for the psA6 and brominated uracil (BrU7) nucleotides is shown, indicating the presence of the ps-JA (blue carbons) and ps-JB (orange carbons) conformers (c) Geometry of the Br···S interaction from the phosphothioate of A6 (yellow sphere) to Br of BrU7 at the junction core of ps-JA. The short distance and angle of approach are labeled for the Br···S interaction, along with distance to the associated water molecule (WA). (d) Geometry of the Br···S interaction at the junction core for ps-JB. The distance and angle of approach are labeled for the Br···S interaction.

a

p-Ja

ps-JA

Junction Parameters 40.7° 30.1° Jtwist Jroll 138.7° 129.6° Rotational Helix Parametersb helical twist (34.7°)c 36.85° 36.90° propeller twist (−12.0°)c −19.90° −12/20° tilt (−0.62°)c 0.15° 0.50° roll (1.74°)c 3.35° 2.60° Buckle (−0.23°)c −7.80° 8.10° Opening 3.10° 4.70° Translational Helix Parametersb rise (3.30 Å)c 3.29 Å 3.21 Å slide (0.66 Å)c 0.75 Å 0.79 Å shear 0.30 Å 0.59 Å stretch 0.12 Å −0.34 Å stagger −0.06 Å −0.60 Å shift 0.03 Å 0.03 Å

p-Ja

ps-JA

ps-JB

rBr···(O/S) %∑rvdW θ1

2.9 Å 86% 167.2°

3.5 Å 96% 161.3°

4.1 Å 112% 150.1°

Parameters for the p-J construct were from structure 2ORG.10

The geometry of the X-bond in ps-JA, however, is longer (in terms of the %Σrvdw) and less linear compared with the analogous Br···O interaction in the previously studied structure (PDB code 2ORG). The less linear angle of approach of the acceptor to the halogen, however, is consistent with results from previous work on sulfur acceptors in small-molecule assemblies,14 where the approach angles fall between 160 and 170°, as compared with those of oxygen acceptors,43 which fall between 170 and 180°. Furthermore, the X-bond of sulfur acceptors in the small-molecule systems has been shown to be more energetically favorable when compared with oxygen acceptors,30 suggesting that the angle of approach may not be as stringent in this large element compared with O. Finally, a water molecule was seen in ps-JA bridging the sulfur acceptor to the Br, which could confer additional stability to this interaction in the junction (Figure 3d). Dif ferential Scanning Calorimetry Comparison of S and O XBond Energies. The effect of the Br···S X-bond on the thermal stability of the junction in solution was determined through DSC melting studies. We had previously shown that junction formation is concentration-dependent, with the DNA remaining as a duplex at low concentrations and as a four-stranded junction at higher concentrations. At the concentration of DNA (300 μM) for the current study, both junction and duplex are present, allowing the melting parameters of the two forms to be determined simultaneously. The DSC melting and cooling profiles of the ps-J construct showed fully reversible melting and reannealing of the DNA and were best fit using two two-state van’t Hoff models. Subtracting the duplex energies from the junction leaves the energy of stabilization associated with the interactions at the junction crossover.35 Subsequent comparison of the crossover energies between ps-J and p-J allows us to determine the specific thermodynamic parameters (ΔΔH25°C, ΔΔS25°C, and ΔΔG25°C) of a sulfur relative an oxygen as an X-bond acceptor. The DSC melting data show that both the junction and duplex forms of the phosphothioate ps-J construct are more

Table 1. Comparison of Overall Junction Parameters (Jtwist and Jroll) and Helix Parameters for the T5·A6 Base Pair at the Crossover of the Phosphate p-J junction Construct and the Two Conformers of the Phosphorothioate (ps-JA and ps-JB) Structures parameter

parameter

ps-JB 30.2° 124.8° 36.95° −19/10° 1.30° −1.50° −17.10° 5.80° 3.27 Å 0.19 Å −0.93 Å 0.12 Å 0.54 Å 0.03 Å

Parameters for the p-J construct were from structure 2ORG.10 bHelix parameters were calculated using CURVES+.41 cValues in parentheses are the averages for all B-type structures from Hays et al.42 a

factors, which were significantly higher for the T5 and A6 residues with only a single model, but became consistent with the remainder of the structure with two conformers in the phasing model. 4248


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Table 3. Melting Temperatures (Tm), Enthalpies (ΔHm), and Entropies (ΔSm) Measured by Differential Scanning Calorimetry (DSC) for the p-J and the Phosphorothioate (ps-J) DNA constructs duplex

junction

DNA

Tm (°C)

ΔHm (kcal/mol)

ΔSm (cal/(mol K))

Tm (°C)

ΔHm (kcal/mol)

ΔSm (cal/(mol K))

p-J ps-J

51.9 ± 0.12 52.6 ± 0.10

53.2 ± 0.5 58.4 ± 0.3

163.5 ± 1.6 179 ± 0.9

57.2 ± 0.08 58.2 ± 0.13

70.7 ± 1.0 83.8 ± 0.6

214 ± 3 253.1 ± 1.8

thermally stable than the native p-J, with melting temperatures (Tm) that are higher by ∼0.7 °C for the duplex and by 1 °C for the junction (Table 3). Furthermore, ΔHm for ps-J duplex and junction is ∼6 and ∼13 kcal/mol, respectively, higher than the comparable oxygen-containing DNA. To directly compare the stabilizing potential of the sulfur Xbond acceptor to that of oxygen, the DSC melting parameters were translated to stabilizing enthalpies and entropies at a reference temperature of 25 °C (ΔH25°C and ΔS25°C, respectively), applying the change in heat capacity (ΔCp) in the standard relationships.44 Because the core structures are nearly identical for the oxygen and sulfur constructs, the difference in ΔH25°C and ΔS25°C reflects the difference in specific X-bonding potential for the two types of acceptors once the effects of the modifications on the duplexes have been accounted for. The resulting thermodynamic values (Table 4) show that the sulfur−bromine X-bond is enthalpi-

Table 5. Quantum-Mechanical Energies Calculated at the MP2 Level (EMP2), Applying the aug-cc-PVTZ Basis Set with BSSE Correction, for a 5-Bromouracil Complex with Dimethylphosphate (for 2ORG) or with Dimethylphosphorothioate (for ps-JA and ps-JB Conformers of the ps-J Construct) EMP2 (kcal/mol)

ΔS25°C(J−D), and ΔG25°C(J−D)), and Associated Differences between the Phosphorothioate and Phosphate Junction Constructs (ps-J−p-J) ΔH25°C(J−D) (kcal/mol)

ΔS25°C(J−D) (cal/(mol K))

ΔG25°C(J−D) (kcal/mol)

DNA construct

−5.6 ± 0.5 −9.1 ± 0.3 ΔΔH25°C (kcal/mol)

−15.6 ± 1.5 −25.7 ± 0.9 ΔΔS25°C (cal/(mol K))

−0.97 ± 0.06 −1.40 ± 0.04 ΔΔG25°C (kcal/mol)

ps-J−p-J

−3.5 ± 0.6

−10.2 ± 1.8

−0.43 ± 0.07

p-J ps-J

Br···S (ps-JA)

Br···S (ps-JB)

−2.22

−1.75

−0.94

the QM calculated and the DSC measured energies. The MP2 energies show that the Br···S X-bond of the ps-JA conformer is about twice as stabilizing as that of ps-JB. This is not surprising, given the shorter and more linear geometry of the ps-JA conformer. In contrast with the DSC results, however, the QM energies for the Br···S X-bond of ps-JA were slightly less stabilizing by ∼0.5 kcal/mol than that of Br···O. Thus the QM energies support the expectation that the more ideal geometry of ps-JA conformer is energetically more stable than the ps-JB conformer and the observation from the DSC studies that the sulfur is comparable to oxygen as an X-bond acceptor. In the current work, we have shown that an anionic sulfur can serve as a favorable acceptor for bromine X-bonds. Although previous studies have characterized the structure− energy relationship of sulfur X-bonds in small-molecule assemblies both experimentally and computationally, there has been a dearth of knowledge about sulfur acceptors in a biological context. In our DNA model system, a bromine Xbond with a sulfur acceptor was shown to be enthalpically more stabilizing than a comparable oxygen acceptor, despite what appears to be less favorable geometries. Both the energetics and broader range of geometries are consistent with prior computational studies on sulfur−halogen interactions.14,30 The stronger interaction, however, comes with an entropic cost, which renders sulfur overall only slightly more stabilizing as an X-bond acceptor. Sulfur-containing amino acids have been observed to comprise only 5% of X-bond acceptors in protein−ligand complexes,8 which may reflect the overall lower occurrence of the element at accessible regions in protein structures. Cysteine and methionine, however, are both prevalent in active sites of enzymes.45 Cysteines, for example, are key reactive nucleophiles for many hydrolases, deubiquitinases, caspases, and enzymes involved in redox reactions.46 Methionine is a particularly interesting in drug design due to its flexibility and lipophilicity. Similar to cysteine, it is found at higher rates in active sites of many enzymes, including nuclear hormone receptors, catechol-O-methyltransferase, and herpes simplex virus type 1 thymidine kinase.47 With the understanding now that sulfur is comparable to or more potent than oxygen as an X-bond acceptor, even in geometries that are not as short or linear, this underrepresented element becomes an attractive target when designing halogenated compounds as therapeutic agents.

Table 4. Stabilization Enthalpies, Entropies, and Free Energies Derived from DSC Melting Studies (Table 3), Extrapolated to 25 °C, for the Junction Minus Duplex Forms of the p-J and ps-J DNA Constructs (ΔH25°C(J−D),

DNA construct

Br···O (2ORG)

cally more stabilizing by −3.5 kcal/mol compared with oxygen. As had been previously seen,51 this more thermally stable interaction comes at an entropic cost of 10 cal/(mol K), which is reflected in the significantly lower crystallographic B-factors of the nucleotides at the junction crossing-overthose that participate in the X-bond (Figure S2). The resulting ΔΔG25°C, however, shows that sulfur remains overall a slightly stronger X-bond acceptor by 0.4 kcal/mol in this DNA system. QM Calculations on X-Bonding Energies. To associate the geometries of the X-bonds seen in the crystal structures with the stabilizing potentials determined by DSC, we performed QM calculations at the MP2 level on a set of model compounds (Figure S3) that mimic the Br···O interaction of the interaction in the previous 2ORG and the Br···S interaction of the current ps-J constructs (Table 5). We note that these MP2 calculations do not take into account the explicit solvent interactions, including the water seen in ps-JA that bridges the sulfur to the Br atom, or base stacking effects, all of which may account for the significant deviations between 4249


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METHODS DNA Synthesis and Purif ication. The DNA constructs for this study were designed as self-complementary sequences of the form 5′-CCGATXBrUCGG-3′ (where X has either a standard 2′-deoxyadenosine 5′-monophosphate, pA, or a 2-deoxyadenosine-5′-thiomonophosphate, psA). Chemically synthesized DNA oligonucleotides are purchased from Midland Certified Reagent Company attached to the solid controlled-pore glass (CPG) support, with the terminal dimethoxytrityl protecting group intact to allow for purification. The full-length product sequences were HPLC-purified and subsequently detritylated, as previously described.10,34 Phosphorothioate constructs required an additional HPLC step to separate the pro-Rp from pro-Rs prochiral enantiomers (Figure 2) using a protocol derived from that as described in Liu et al.48 Crystallization and Structure Determination. DNA constructs were crystallized by hanging drop vapor diffusion under conditions similar to those used previously to crystallize brominated DNA junctions.10 The initial 6 μL crystallization drops contained 0.75 mM DNA, 25 mM sodium cacodylate buffer (pH 7.0), 10−20 mM calcium chloride, and 0.9−1.2 mM spermine. Thin diamond-shaped crystals of the p-J and the pro-Rp ps-J enantiomer grew after 7 days of equilibration against a reservoir containing 30% 2-methyl-2,4-pentanediol for both constructs and 1% ß-mercaptoethanol for the psA construct. X-ray diffraction data on DNA crystals were collected using a Rigaku Compact Home Lab equipped with a copper sealedtube microfocus source and a PILATUS detector. Data were indexed, integrated, and scaled using the HKL2000 program (Table S1). Crystal structures were solved by molecular replacement using PHENIX,49 with a brominated junction (Protein Data Bank, PDB50 code 2ORG10) in which the bromine had been removed, serving as the initial phasing model. The final model (PDB code 5VBJ) was refined to Rcryst = 21.8% and Rfree = 27.6%. Dif ferential Scanning Calorimetry Studies. DSC was performed to determine energies of the sulfur-containing and non-sulfur-containing constructs, as previously described.34,35 DNA constructs (300 μM concentration in a solution containing 50 mM sodium cacodylate buffer, pH 7.0, and 15 mM calcium chloride) were annealed in the DSC instrument (TA Instruments Nano DSC) by heating to 90 °C for 20 min then allowing to cool to 10 °C at a rate of 0.9 °C/min. DNA melting energies were collected in the DSC, starting with equilibration for 400 s, and scanning from 10 to 95 °C at a rate of 0.9 °C/min at a pressure of 3.0 atm. Melting temperatures (Tm) and enthalpies of melting (ΔHm) were determined by fitting the data with TA Nano Analyze software. Previous work34,51 showed the presence of both junction and duplex for 300 μM DNA concentrations; therefore, a two-component (junction and duplex), two-state scaled model was used to analyze the data (Figure S1). Data for each construct were measured for at least seven replicates. Quantum-Mechanical Calculations. Models for QM energy calculations of the X-bonded junctions consisted of a 5brominouracil base interacting with either (dimethylphosphate) for the p-J construct or dimethylphosphorothioate (for the ps-J construct), with atomic position placed according to their respective crystal structures (Figure S2). The Møller− Plesset second-order (MP2) QM energies were calculated using Gaussian 09,52 with cyclohexane as the solvent (D = 2,

relative to a vacuum) to mimic the hydrophobic environment of the junction core, applying an appropriate polarizable basis set that includes dispersion (aug-cc-PVTZ) from the EMSL Basis Set Exchange.53 Basis set superposition errors (BSSEs) were determined from a separate counterpoise gas-phase calculation and directly summed into the calculated solvent phase energy.54

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpclett.7b01725. Table S1. Parameters from Crystallization and Structure Solution of ps-J (PDB code 5VBJ). Figure S1. Sample differential scanning calorimetry (DSC) melting profile. Figure S2. Molecular models for QM calculations of Xbond interaction energies. Table S2. Atomic coordinates of the 5-bromouracil-dimethylphosphate complex for quantum-chemical calculations of Br···O X-bonding interaction. Table S3. Atomic coordinates of 5bromouracil-dimethylphosphorothioate complex for quantum-chemical calculations of Br···S X-bonding interaction in ps-JA conformation. Table S4. Atomic coordinates of 5-bromouracil-dimethylphosphorothioate complex for quantum -chemical calculations of Br···S Xbonding interaction in ps-JB conformation. (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: 970-491-0569. Fax: 970491-0494. ORCID

Melissa Coates Ford: 0000-0002-0253-5389 P. Shing Ho: 0000-0002-8082-4311 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by a grant from the National Science Foundation (CHE-1608146). REFERENCES

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Sulfur as an Acceptor to Bromine in Biomolecular Halogen Bonds

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