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How do Distance and Solvent Affect the Halogen Bonding Involving Negatively Charged Donors? Zhaoqiang Chen, Guimin Wang, Zhijian Xu, Jinan Wang, Yuqi Yu, Tingting Cai, Qiang Shao, Jiye Shi, and Weiliang Zhu J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.6b05027 • Publication Date (Web): 09 Aug 2016 Downloaded from http://pubs.acs.org on August 13, 2016

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The Journal of Physical Chemistry

How do Distance and Solvent Affect the Halogen Bonding Involving Negatively Charged Donors? Zhaoqiang Chen,†,≠,# Guimin Wang,†,≠,# Zhijian Xu,*,†,⊥,≠ Jinan Wang,†,≠ Yuqi Yu,†,≠ Tingting Cai†,≠ Qiang Shao,†,≠ Jiye Shi,*,§ Weiliang Zhu*,†,≠ †

CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of

Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China §

UCB Biopharma SPRL, Chemin du Foriest, B-1420 Braine-l'Alleud, Belgium

⊥

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia

Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China ≠

University of Chinese Academy of Sciences，No.19A Yuquan Road, Beijing 100049, China

*To whom correspondence should be addressed. Phone: +86-21-50806600-1201 (Z.X.), +32-2-3862861 (J.S.), +86-21-50805020 (W.Z.), Fax: +86-21-50807088 (W.Z.), E-mail: [email protected] (Z.X.), [email protected] (J.S.), [email protected] (W.Z.). #

These authors contributed equally to the work.

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ABSTRACT: It was reported that negatively charged donors can form halogen bonding, which is stable, especially, in polar environment. By survey in Protein Data Bank, we noticed that the distance between negative charge center and the halogen atom of an organohalogen may vary greatly. Therefore, a series of model systems, composed of 4-halophenyl conjugated polyene acids and ammonia, were designed to explore potential effect of the distance on the halogen bonding in different solvents. Quantum mechanics calculations demonstrated that the longer the distance, the stronger the bonding. The energy decomposition analysis on all the model systems demonstrated that the electrostatic interaction makes the most contribution (44-56%) to overall binding, followed by orbital interaction (42-36%). NBO calculations showed that electron transfer takes place from the acceptor to the donor while the halogen atom becomes more positive during the bonding, which is in agreement with the result of neutral halogen bonding. QM/MM calculations demonstrated that the polarity of binding pockets makes all the interactions be attractive in protein system. Hence, the strength of the negatively charged halogen bonding could be adjusted by changing the position of the negative charge center to halogen atom and the environment that the bonding exists in, which may be applied in material and drug design for tuning their function and activity.

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Introduction Halogen bonding (XB) is a noncovalent interaction between organohalogen and nucleophilile, in which the halogen atoms (usually Cl, Br and I) interact with nucleophilile by their positive regions on the surface of halogen.1-6 It is prevalent in the Cambridge Structural Database (CSD)7-8 and Protein Data Bank (PDB)9-11, which has become a subject of great interest in some fields, such as drug design4,9,11-15 and material science1,4,12-13,16. The interaction energies of halogen bonding are comparable with hydrogen bonding, varying from 5 kJ/mol to 180 kJ/mol.17 The strength of halogen bonding (R-X···Y) is found to be affected by a number of factors. Firstly, halogen bonding strength increases as the electron-withdrawing ability of the substituent (R) in the organohalogen increases.18-21 Secondly, the more electronegative the halogen bonding acceptor (Y) is, the stronger the halogen bonding becomes.22 Moreover, the halogen bonding strength increases as the halogen (X) changes from Cl to Br and I.21,23-24 Comparing with hydrogen bonding, halogen bonding is more directional for the anisotropic of electron distribution of the halogen.4,7,17,25-26 Stone and Hill found that the directivity of halogen bonding is attributed to exchange-repulsion rather than electrostatic interaction.27-28 The main driving forces of halogen bonding were reported to be electrostatic and dispersion term according to the energy decomposition analysis with symmetry adapted perturbation theory (SAPT).29 Moreover, the total interaction energy has a similar magnitude to the dispersion term.28 Recently, the additive and synergistic effects between halogen bonding and other noncovalent interactions,25,30-35 such as cation⋅⋅⋅π interaction, S⋅⋅⋅N interaction, anion⋅⋅⋅π interaction, hydrogen bonding, were also studied. Clark and Politzer found that the electrostatic potential (ESP) surface of halogen atoms contain an positive area along the extensions of the covalent bond (R-X), as shown in Figure 1a, which is called sigma-hole.36 Studies indicated that there is a positive correlation between the halogen bonding strength and the electropositivity (VS,max) of the sigma-hole, the VS,min in the halogen bonding acceptors, and the

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product of VS,max and VS,min.4,22,37-38 Murry found that not only relative electron attracting power but also relative charge capacity (polarizability) affects the magnitude of the sigma-hole on the electrostatic potential.39 However, all the molecules mentioned in the above studies were neutral with positive VS,max values on the surfaces of the halogen atoms. We demonstrated that the ESP all over the surfaces of negatively charged organohalogen molecules turns to be negative, including the VS,max on the halogen atoms (Figure 1b).40 Accordingly, halogen bonding with negatively charged donors is unstable or metastable in vacuum, but the interaction becomes attractive in the protein environment. Our further analysis showed that the distance of the negative charge center of the organohalogen to the halogen atom (called NQ-X distance hereinafter) could be different both geometrically and topologically. However, to the best of our knowledge, there is no systematic study on the effect of the NQ-X distance on the strength of the halogen bonding with negatively charged donors (called negative halogen bonding hereinafter). We then carefully searched PDB and found that the distance between the anionic groups, e.g., carboxyl, and halogen atoms varies from 3 to 14 Å. Accordingly, some questions were raised. How does the distance affect the sigma-hole of the halogen atom and the halogen bonding strength? How does the solvent or environment affect the halogen bonding strength versus the distance? What is the main driving force of the negative halogen bonding? In order to get some insight into these questions, we carried out a systematic database survey and computational chemistry study. QM calculations were performed on both model systems and protein-ligand systems extracted from PDB. The interaction energies were decomposed by the combination of extended transition state energy decomposition analysis and the natural orbitals for chemical valence (ETS-NOCV) method. Natural bond orbital (NBO) theory and quantum theory of atoms in molecules (QTAIM) analysis were also carried out.

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Figure 1. Electrostatic potentials mapped on the molecular surfaces of neutral (a) and negatively charged (b) halogen bonding donor (4-bromobenzoic acid and its anion, electron density is 0.001a.u.). METHODS Database Survey for Halogen bonding with Negatively Charged Donors The protein structures in PDB were surveyed for the negative halogen bonding. According to the definition of the halogen bonding by IUPAC,41 the acceptors may be atoms with lone pair, π system or anions. Here, we only consider the halogen bonding (C-X···Y) with the small organohalogen molecules containing carboxyl acting as the halogen bond donor, and the atoms containing lone pair electrons acting as the halogen bond acceptor (Y), as shown in Figure 2. We carried out the survey with following criteria: the X···Y distance (d) should be shorter than the sums of the vander Waals (vdW) radii of X and Y, i.e., d(Cl···O) < 3.27 Å, d(Br···O) < 3.37 Å, d(I···O) < 3.50 Å, d(Cl···N) < 3.30 Å, d(Br···N) < 3.40 Å, d(I···N) < 3.53 Å, d(Cl···S) < 3.55 Å, d(Br···S) < 3.65 Å, d(I···S) < 3.78 Å and the C-X···Y angles (θ) should be larger than 140° (Figure 2).

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Figure 2. The structure of negative halogen bonding and criteria for database survey. X represents halogen atoms, viz. Cl, Br and I; Y represents O, N, S atom. θ represents the halogen bonding angle, d represents the halogen bonding length; Y is halogen bond acceptor. QM Calculation for the Model Systems To investigate how the NQ-X distance affects the halogen bonding, we designed a series of model complexes, i.e., -OOC-(C=C)n-ph-X (n=0-5; X=Br, I) as the halogen bonding donors and ammonia (NH3) as the halogen bond acceptor (Figure 3). Chlorine atom is not included in this study because the negative halogen bonding is too weak to be undisturbed by other interactions (Figure S1, Supporting Information). The angles (C-X···N) of the complexes were initially set to be 180° in the model complexes. It has been reported that M06-2X method gives good performance for halogen bonding interaction.42 As the systems in this study is negatively charged, we compared different DFT approaches, viz., B3LYP, ωB97X-D and M06-2X with MP2 method, which suggested that M06-2X is a reasonable method for the study (Table S1, Supporting Information). Therefore, these complexes were optimized by the method of M06-2X function with the pseudo-potential based Stuttgart/Dresden (SDD) basis set for iodine and 6-311++G(d,p) basis set for other atoms. To confirm that the optimized geometries corresponded to energy minima, the harmonic vibrational frequencies calculations were also performed at the same level. Protein has anisotropic environment in terms of dielectric constant. The local dielectric constant of the binding pocket of a protein could vary from 4 to 80 depending on its position and the residues constituting the pocket.43-44 To mimic various environments in a protein, the conductor-like polarizable continuum model (CPCM) was applied in the calculations with different solvents,45 i.e., chlorobenzene (ε=5.6), dichlorobenzene (ε=10.4), acetone (ε=20.5), DMSO (ε=46.8) and water (ε=78.4). The basis set superposition error were taken into account in the interaction energies by the counterpoise method.46 The details of interaction energy calculation scheme can be found in the ref 40. All these calculations 6


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were carried out using Gaussian 09 suite of program.47

Figure 3. The schematic for negative halogen bonding in model systems. ESP on Molecular Surface The noncovalent interaction energy was reported to have a good correlation with the electrostatic potential, especially, for the interactions dominated by electrostatic.2,4,39,48-50 ESP was calculated in this study with the same method as refs 39 and 40. The electrostatic potentials presented in this work were computed using the Multiwfn (v 3.3.5) software,51 with the wave functions obtained by Gaussian 09 suite. QTAIM Analysis QTAIM was originally introduced by Bader, which can be applied to analyze the noncovalent interactions.52-56 The following properties, i.e., the electron density (ρ) and the negative Laplacian of the electron density (L) at the bond critical points (BCPs) were demonstrated to be highly correlated to the interaction strength. We computed these properties by using Multiwfn (v 3.3.5), with the wave functions obtained with Gaussian 09 suite. Energy Decomposition Energy decomposition was performed using the ETS-NOCV approach with ADF on the optimized structures.57-63 The studied complexes were divided into two fragments, the halogen bond donors and the halogen bond acceptors. Dispersion was then taken into consideration by using the dispersion corrected BP86-D method. The total binding energy can be described as following equation 1.

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∆ E int = ∆ E elest + ∆ E pauli + ∆ E orb + ∆ E disp

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(1)

NBO analysis The NBO calculation has been deemed as a useful tool to analyze the noncovalent interactions.54-55,64-67 The second-order perturbation stabilization energy E(2) is an important indicator to evaluate the strength of a noncovalent interaction, which was calculated using the same method as ref 69. To get further insight into negative halogen bonding, NBO-based analysis was performed on the monomers and complexes at the M06-2X/6-311++G(d,p)/SDD level by the use of the NBO program implemented in the Gaussian 09 package. QM/MM Calculation To explore how the distance affect the halogen bonding in protein systems, we performed QM/MM calculation by using a two-layer our own N-layered integrated molecular orbital and molecular mechanics (ONIOM) method.68-70 Four crystal structures in PDB, viz., 3GT3, 3LD5, 3E3T and 1PGG, were selected for the calculation, which contain negative halogen bonding with different distances between the negative charge centers and the halogen atoms in the organohalogen molecules (Figure 4). The ligands and the corresponding residues around the halogen atoms were treated as the QM region (Figure 4), while the other atoms were left in the MM layer. Hydrogen atoms were added to the ligands by LigPrep71 at the pH values of the crystallization. The protonated state of the proteins residues were predicted using the H++ website at the same pH values.72 The QM region was described using M06-2X method, with SDD basis set for the iodine atom and 6-31G(d) for the other atoms during optimization; the MM layer was described by the AMBER parm96 force field. The single point energies were calculated with M06-2X method and 6-311++G(d,p)/SDD basis sets.

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Figure 4. The negative halogen bonding in protein systems of (a) 3GT3, (b) 3LD5, (c) 3E3T and (d) 1PGG. Atoms in the QM layer are presented as sticks with carbon atoms in green for ligands and gray for proteins, oxygen atoms in red, nitrogen atoms in blue, bromine atoms in crimson, and iodine atoms in purple. Atoms in the MM layer are shown as cartoon.

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RESULTS AND DISCUSSION Searching for Negative Halogen Bonding in PDB The PDB (July 2015 release) have 12,955 crystal structures containing halogen atoms, among which 350 negative halogen bondings (Table S2, Supporting Information) were found by filtering these structures with the negative halogen bonding criteria as shown in Figure 2. We analyzed the distances between the halogen atom and the anionic oxygen in these crystal structures. The distance varies from 3 to 14 Å, with a peak at 5-9 Å (Figure 5). Accordingly, we designed 12 model systems (Figure 3) to explore the distance and solvent effect on negative halogen bonding with QM calculations.

Figure 5. Proportion of negative halogen bond donors at different distances involved chlorine (a), bromine (b), iodine (c) and the sum of all the halogen atoms (d). The distance is the average of the 10


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distances between two anionic O atoms on the carboxylate and the halogen atom. Optimized Geometry and Predicted Binding Energy for the Model Systems The model complexes were optimized in vacuum and various solvents for mimicking different protein environment, ending with the angles (C-X···N) close to 180° and halogen bonding length (X···N) shorter than the sum of the vdW radii of the corresponding atoms (Figure S2, Supporting Information). Figure 6 depicts the interaction energy change versus topological distance and dielectric constant. The details of the optimized geometry parameter and interaction energies in the solvents chlorobenzene and water, which are used for mimicking the inner environment and polar binding pocket of protein system, are summarized in Table 1 (the data about all solvents are in Table S3 in Supporting Information).

Figure 6. Interaction energies for negative halogen bond include iodine (a) and bromine (b) in different distance and solvents (white color stands for unstable complex system). Table 1. Calculated Binding Energies and Geometry Parameters of Model Systems in Different Solvents solvents (ε) p-HCOO-phX…NH3f p--COO-phX…NH3f

Vacuum (0)

a

n

db

0 0 0 1 2 3 4

7.10 9.41 11.80 14.15 16.54

I bc 3.10 3.30 3.26 3.19 3.16 3.15 3.14

Br θd 179.8 179.9 179.9 179.2 179.1 179.3 179.3

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∆Ee -4.20 -0.31 -0.22 -1.52 -2.12 -2.48 -2.74

bc 3.11 3.16 3.15 3.14

θd 179.8 179.6 177.4 178.6

∆Ee -2.31 -0.38 -0.74 -0.96


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Chlorobenzene (5.6)

Water (78.4)

5 0 1 2 3 4 5 0 1 2 3 4 5

18.95 7.11 9.42 11.79 14.19 16.60 19.03 7.11 9.42 11.79 14.20 16.61 19.04

3.13 3.12 3.08 3.07 3.07 3.07 3.07 3.08 3.06 3.06 3.06 3.06 3.06

179.2 179.9 179.8 179.9 179.8 179.8 179.9 180.0 179.8 179.9 179.9 179.8 179.9

-2.94 -2.00 -2.38 -2.53 -2.62 -2.66 -2.69 -2.31 -2.51 -2.55 -2.56 -2.55 -2.54

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3.13 3.15 3.15 3.15 3.13 3.13 3.14 3.15 3.15 3.14 3.13

178.8 179.8 179.2 178.4 179.8 179.5 179.8 179.2 178.0 179.0 179.3

-1.14 -0.69 -0.74 -0.82 -0.87 -0.91 -0.78 -0.80 -0.77 -0.78 -0.79

a

The topological distance between the benzene and the carboxyl. bThe physical distance between the halogen atom and the carboxyl. cThe length of halogen bond, Values are in angstrom. dThe angle of halogen bond, Values are in degree. eValues are in kcal/mol. fThe neutral system and the negative system in vacuum, the data come from reference 40. -Could not get reasonable geometry of the complex.

As we all know, neutral halogen bonding strength increases as the following order: Cl < Br < I. In the negative halogen bonding systems, the interaction strength increases in the same order both in vacuum and solvents, but is weaker than that of neutral systems even if the topological distance is as far as n=5 in vacuum (Table 1). Effect of Topological Distance on the Strength of Negative Halogen Bonding In the model systems, the physical distances have a good linear relationship with the topological distances (Table 1). Therefore, the topological distance was used for further analysis. For the systems in vacuum, the data showed that the halogen bonding interaction becomes stronger as the topological distance increases from n=0 to 5. With data fitting, we found an apparent exponential relationship between the halogen bonding strength and the topological distance (n), as shown in Figure 7. The relationship can be described by the equations 5 and 6 for the iodine and bromine systems, respectively. ∆EIodine = 2.81* e ( − n /1.78) − 3.06

(5)

∆EBromine = 2.36 * e ( − n /2.65) − 1.49

(6)

Where ∆E is the interaction energy and n is the topological distance (Figure 3). The equations 5 and 6 have strong correlation coefficient with R2 values of 0.996 and 0.998, respectively, suggesting high reliability. The results revealed that the halogen bonding interaction gets strengthened as the topological 12


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distance of the negative charge center to the halogen atom elongated. From the two equations, the limit values of ∆E are -3.06 and -1.49 kcal/mol for the iodine and bromine systems, which is still weaker than the strength of neutral halogen bond (Table 1).40 The energy attenuation damping index for the iodine (1/1.78=0.56) is bigger than that for the bromine system (1/2.65=0.38), suggesting the negative halogen bonding of iodine is more sensitive than that of bromine to topological distance. Obviously, the effect of the topological distance on the binding strength becomes weaker and weaker as n increases. Taking 4iodophenyl conjugated polyene acids as example, moving from n=0 to 1, 1.30 kcal/mol increase was observed while 0.6 kcal/mol increase was observed when n changes from 1 to 2. Only 0.2 kcal/mol difference was observed between n=4 and 5. On the whole, there is 2.8 kcal/mol effect of the NQ-X distance on the binding energy from n=0 to 5. The strength of negative halogen bond is more close to the neutral halogen bonding as the distance increase.40 Similar change was observed for 4bromophenyl conjugated polyene acids system with a small difference (< 1.0 kcal/mol) between the negative (n=5) and the neutral halogen bonding.40 Accordingly, the effect of a negative charge center on halogen bonding strength with topological distance as far as 5 is almost negligible.

Figure 7. The relationship between energy and distance for organoiodine complexes (a), organobromine complexes (b) in vacuum. Effect of Solvents on the Strength of Negative Halogen Bonding 13



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To provide in-depth information on the solvent effect, we calculated the interaction energies in different solvents. The interaction energies in water were compared with that in vacuum. The interaction energy for the organoiodine complex is -0.22 kcal/mol in vacuum while that is -2.31 kcal/mol in water when n is 0 (Table 1, Figure S3a, Supporting Information). In contrast, when n is 5, the halogen bonding interaction for the organoiodine complex is -2.94 and -2.54 kcal/mol in vacuum and water, respectively. Similar trends were observed for the organobromine complex (Table 1, Figure S3b, Supporting Information). In conclusion, the solvent could enhance the negative halogen bonding with short topological distance (n≤2) more significantly than that with long topological distance (n>2). In addition, the interaction energies in different solvents were compared. The energy difference is very small in different solvents, especially for the bromine system (Figure 6). Electrostatic surface potential of the negative halogen bond donors It is well known that the “sigma-hole” of neutral organohalogen compounds is positive in terms of VS,max of the hole. When the organohalogen compounds are negatively charged, the electron-deficient region remains, but the VS,max value becomes negative. The VS,max values of the halogen atoms in the organohalogen compounds we studied are calculated and summarized in Table 2 (more details are in Table S4, Supporting Information). Table 2. VS,max Values and Interaction Energies of the Compounds with Different Topological Distances in Vacuuma I n

a

Br

0 1

VS,max -31.96 -20.89

∆E -0.22 -1.52

VS,max -41.13 -30.27

∆E -

2

-14.38

-2.12

-23.77

-0.38

3

-9.86

-2.48

-19.21

-0.74

4

-6.31

-2.74

-15.71

-0.96

5

-3.42

-2.94

-12.81

-1.14

All the values are in kcal/mol. -Could not get reasonable geometry of the complex.

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As expected, the VS,max values of the negatively charged organohalogen compounds on the iodine atom are still greater than that on the bromine atom in the same solvent. The VS,max increases as the topological distance (n) becomes larger. There is an apparent exponential relationship between the VS,max and the topological distance (Figure 8a). For the negative halogen bonding, the halogen bonding strength is still have a good linear relationship with the VS,max in vacuum, as shown in Figure 8b.

Figure 8. The relationship between VS,max and topological distance (a) or interaction energy (b). QTAIM analysis The results of QTAIM analysis were summarized in Table 3 (BCPs are showed in Figure S4 and S5, solvent data are described in Tables S5 and S6, Supporting Information). The values of ρ range from 0.0116 to 0.0173 a.u. for negative halogen bonding, which is consistent with the hydrogen bonding ranges suggested by Koch and Popelier (0.002-0.035 a.u.).73-74 The positive values of ρ, ∇²ρ, Gb, Hb and |Vb|/Gb for all the complexes indicated the closed-shell nature of the interactions. The sign of Hb depends upon whether the interaction is electrostatic dominant (Hb > 0) or covalent dominant (Hb < 0). Accordingly, the positive values of Hb imply that the negative halogen bonding interactions are still driven by electrostatic interaction. All these parameters, i.e., ρ, ∇²ρ, |Vb|, Gb and |Vb|/Gb increase as the distance increases, suggested that the binding is getting stronger and stronger with the increase of the topological distance in vacuum. 15



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Table 3. The Topological Parameters at BCPs of Negative Halogen Bonding in Vacuuma X Br

I

a

n 2 3 4 5 0 1 2 3 4 5

ρ 0.0116 0.0119 0.0122 0.0123 0.0120 0.0134 0.0141 0.0145 0.0148 0.0150

Vb -0.0071 -0.0073 -0.0075 -0.0076 -0.0074 -0.0085 -0.0091 -0.0094 -0.0096 -0.0098

∇²ρ 0.0374 0.0384 0.0392 0.0397 0.0368 0.0415 0.0435 0.0447 0.0458 0.0462

Gb 0.0082 0.0085 0.0086 0.0088 0.0083 0.0095 0.0100 0.0103 0.0105 0.0107

Hb 0.0011 0.0014 0.0015 0.0016 0.0009 0.0009 0.0009 0.0009 0.0009 0.0009

|Vb|/Gb 6.3151 6.4105 6.5025 6.5651 0.8907 0.9033 0.9091 0.9126 0.9151 0.9173

ρ is the electron density, ∇2ρ is Laplacian of the electron density, H is the total energy density which is the summation of density of

potential energy V and Lagrangian form of kinetic energy density G. ρ,∇2ρ, H, V and G are in atomic units, |V|/G dimensionless.

Energy Decomposition Analysis The total energies and the decomposed components were summarized in Table 4. It is worth noting that the total interaction energies calculated with the ETS-NOCV method gives excellent agreement with that using M06-2X/6-311++G(d,p) method (Table 4 and Figure S6, Supporting Information). For negative halogen bonding, the electrostatic is still the significant attraction, while the dispersion term contributes a little in the ETS-NOCV analysis. In addition, the orbital interaction energy also makes more than 35% contribution to the total attractive interactions. In a word, the electrostatic and orbital interactions play key roles in the negative halogen bonding. Apart from the ETS-NOCV analysis, we also decomposed the energy based on the SAPT theory using the PSI4 software (Table S7, Supporting Information).75 The electrostatic interaction derived from SAPT is almost identical to that obtained by ETS-NOCV method, which implies the reliability of the energy decomposition. When the topological distance increases, all the three attractive terms, viz., electrostatic, orbital and dispersion strengthen, while only the contribution of electrostatic increases. All the results imply that distance effect on the interaction energy was mainly functioned by the electrostatic energy.

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Table 4. ETS-NOCV Interaction Energy Decomposition of the Negative Halogen Bondinga

X

Br

I

a

n

Epauli

Eelstat

Eorb

Edisp

∆Eb

2 3 4 5 0 1 2 3 4 5

4.50 4.72 4.90 5.03 5.72 7.08 7.70 8.09 8.36 8.60

-2.38(44.3%) -2.78(47.3%) -3.06(48.7%) -3.28(49.9%) -2.85(44.6%) -4.54(51.9%) -5.37(54.1%) -5.89(55.3%) -6.26(55.9%) -6.57(56.4%)

-2.28(42.4%) -2.38(40.5%) -2.49(39.6%) -2.56(38.9%) -2.69(42.1%) -3.32(37.9%) -3.64(36.7%) -3.85(36.1%) -4.01(35.8%) -4.15(35.6%)

-0.71(13.2%) -0.72(12.2%) -0.73(11.6%) -0.73(11.1%) -0.85(13.3%) -0.89(10.2%) -0.91(9.2%) -0.92(8.6%) -0.93(8.3%) -0.93(8.0%)

-0.88 -1.17 -1.38 -1.54 -0.67 -1.67 -2.22 -2.58 -2.84 -3.05

All values are given in kcal/mol. bBond energies calculated by the ETS-NOCV method with ADF.

NBO analysis The NBO analysis has been applied in the exploration of noncovalent interactions. The value of charge (q), charge transfer (QCT), and the second-order perturbation stabilization energies (E(2)) are listed in Table 5. The positive value of QCT indicates electrons flow from the ammonia to the halogen donor. The positive value of ∆q(X) indicated electrons flow from the halogen atom to other part in the halogen bond donor. According to the NBO results, the main intermolecular orbital interaction is the interaction between the lone pair of nitrogen atom and formally empty antibonding orbital of the C−X bond. The q(X), QCT and E(2) increase as the distance elongates. Table 5. Calculated Charge and Second-Order Perturbation Stabilization Energies in Natural Bond Orbital Analysis X Br

I

n 2 3 4 5 0 1 2 3

q(X)amono 0.033 0.041 0.046 0.050 0.093 0.124 0.139 0.148

q(X)bcomplex 0.065 0.072 0.077 0.081 0.132 0.163 0.178 0.187

∆q(X)c 0.032 0.031 0.031 0.031 0.039 0.039 0.039 0.039

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QCTd 0.0094 0.0100 0.0106 0.0110 0.0130 0.0168 0.0189 0.0202

E(2)e 2.71 2.84 2.96 3.05 3.32 4.07 4.43 4.67


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4 5 a

0.155 0.160

0.194 0.198

0.039 0.038

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0.0212 0.0220

4.84 4.98

Charge of halogen atoms in halogen bond donors in monomer. bCharge of halogen atoms in halogen bond donors in complex. cDifference

in atomic charge on halogen atoms between the complex and monomer. dCharge transfer from halogen bonding acceptor to donor. All charges are given in a.u.. eSecond-order perturbation stabilization energies of the natural bond orbital interaction between the occupied lone pair of N atom and the formally empty antibonding orbital of C-X bond.

QM/MM calculation Four crystal structures, i.e., 3GT3, 3LD5, 3E3T and 1PGG were selected as examples to give more light on negative halogen bondings in biomacromolecules. Superposition of the heavy atoms in the QM layer between the crystal structures and the QM/MM optimized structures resulted in RMSD values of 1.56, 0.37, 1.03 and 0.79 Å for 3GT3, 3LD5, 3E3T and 1PGG, respectively, suggesting that the optimization result is acceptable. The interaction energies between the ligands and the residues in the QM region are more than -10 kcal/mol, which may contain some other noncovalent interaction, such as π-π interactions (Figure S7, Table S8, Supporting Information). To obtain the negative halogen bonding interaction energies, key fragments reflecting the halogen bond were extracted from the QM region, shown as green sticks in Figure 9. The interaction energies are listed in Table 6. For the weak halogen bonding systems with short physical distance, i.e., 3GT3 and 3E3T, the solvents can enhance the interactions, while for the strong halogen bonding systems with long physical distance, i.e., 3LD5 and 1PGG, the solvents can weaken the interactions. For example, the halogen bonding energy for the 3E3T is 3.33 and -1.75 kcal/mol in the vacuum and water, respectively. So the solvent environment strengthens the bonding by 5.08 kcal/mol. In contrast, for 1PGG, the solvent environment weakens the halogen bonding by 0.6 kcal/mol, changing from the -2.96 kcal/mol in vacuum to the -2.36 kcal/mol in water. These discoveries are in consistent with the conclusions derived from model systems calculation.

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Figure 9. The structure of QM region in the ONIOM model. The atoms displayed in green stick form were selected to calculate the halogen bonding energy. Halogen atoms in 3GT3 (a) and 3LD5 (b) are bromine. Halogen atoms in 3E3T (c) and 1PGG (d) are iodine. Table 6. Halogen Bonding Energies of QM layer PDB ID 3GT3 3LD5 3E3T 1PGG a

X Br Br I I

Acceptor atom O(Ser247) O(Ser113) O(Leu141) O(Leu384)

distancea 3.59 8.80 3.59 11.20

ΔEvacuumb -0.50 -0.96 3.33 -2.96

ΔEwaterb -0.98 -0.53 -1.75 -2.36

Values are given in angstrom. bValues are given in kcal/mol.

Conclusions By survey for negative halogen bond in PDB, 350 negative halogen bonding interactions were found to

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have different NQ-X distance. The distance may vary from 3 Å to 14 Å, with a peak at 5-9 Å. QM calculations revealed that there is an apparent exponential relationship between the halogen bonding strength and the topological distance in vacuum. Taking 4-iodophenyl conjugated polyene acids as example, QM calculations revealed that the binding energy changes from -0.2 to -2.9 kcal/mol as the topological distance increases from n=0 to 5 in vacuum, similar trends were also observed in various solvents but with smaller range from -2.0 to -2.7 kcal/mol. The calculated binding energies in different solvents demonstrated that the solvent can enhance the strength of weak halogen bonding and weaken strong halogen bonding. The ESP surfaces revealed that the VS,max values of the organohalogen anions are always negative no matter how long the topological distance is, but the VS,max increases as the distance increases. QTAIM analysis revealed the closed-shell nature of the interactions, which is mainly driven by electrostatic, the calculated parameters (ρ, ∇²ρ, |Vb|, Gb and |Vb|/Gb) have strong correlation with the strength of the halogen bonding. Furthermore, energy decomposition analysis revealed that electrostatic and orbital interactions play important roles in the negative halogen bonding, making contributions of 44-56% and 42-36%, respectively, to the overall binding strength when the topological distance changes from n=0 to 5. Natural bond orbital (NBO) analysis found that the charge on the halogen atom is positive, which can explain why the negative halogen bond donors can attract ammonia. In conclusion, the strength of the negatively charged halogen bonding could be adjusted by changing the position of the negative charge center and the environment that the bonding exists in, which may be applied in material and drug design for tuning their function and activity.

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Acknowledgements This work was supported by National Natural Science Foundation of China (81273435&81573350), International Science &Technology Cooperation Program of China (2014DFA31130), the State Key Laboratory of Bioactive Substance and Function of Natural Medicines (GTZK201604) and Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (the second phase). ASSOCIATED CONTENT Supporting Information Available: Organochlorine system, Optimized geometries, BCPs position, VS,max, topological parameters and Interaction Energies in Solvents, survey results of PDB, the geometry and interaction energy of QM region in the ONIOM model, This material is available free of charge via the Internet at http://pubs.acs.org.

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Figure 1. Electrostatic potentials mapped on the molecular surfaces of neutral (a) and negatively charged (b) halogen bonding donor (4-bromobenzoic acid and its anion, electron density is 0.001a.u.). Figure 1 170x46mm (300 x 300 DPI)



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Figure 2. The structure of negative halogen bonding and criteria for database survey. X represents halogen atoms, viz. Cl, Brand I; Y represents O, N, S atom. θ represents the halogen bonding angle, d represents the halogen bonding length; Y is halogen bond acceptor. Figure 2 25x8mm (300 x 300 DPI)


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Figure 3. The schematic for negative halogen bonding in model systems. Figure 3 80x33mm (300 x 300 DPI)



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Figure 4.Thenegative halogen bonding in protein systems of (a) 3GT3, (b) 3LD5, (c) 3E3T and (d) 1PGG. Atoms in the QM layer are presented as sticks with carbon atoms in green for ligands and gray for proteins, oxygen atoms in red, nitrogen atoms in blue, bromine atoms in crimson, and iodine atoms in purple. Atoms in the MM layer are shown as cartoon. Figure 4 170x164mm (300 x 300 DPI)


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Figure 5. Proportion of negative halogen bond donors at different distances involved chlorine(a), bromine (b), iodine (c) and the sum of all the halogen atoms (d). The distance is the average of the distances between two anionic O atoms on the carboxylate and the halogen atom. Figure 5 170x134mm (300 x 300 DPI)



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Figure 6.Interaction energies for negative halogen bond include iodine (a) and bromine (b) in different distance and solvents. For the bromine system, as the reasonable geometry of complex can’t be obtained, the grid was colored white. Figure 6 152x48mm (300 x 300 DPI)


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Figure 7. The relationship between energy and distance for organoiodine complexes (a), organobromine complexes (b) in vacuum. Figure 7 170x62mm (300 x 300 DPI)



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Figure 8. The relationship between VS,max and topological distance (a) or interaction energy (b). Figure 8 170x63mm (300 x 300 DPI)


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Figure 9. The structure of QM region in the ONIOM model. The atoms displayed in green stick form were selected to calculate the halogen bonding energy. Halogen atoms in 3GT3 (a) and 3LD5 (b) are bromine. Halogen atoms in 3E3T (c) and 1PGG (d) are iodine. Figure 9 170x148mm (300 x 300 DPI)



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Table of Contents Table of Contents 85x27mm (300 x 300 DPI)


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How Do Distance and Solvent Affect Halogen ... - ACS Publications

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