Unstable, Metastable, or Stable Halogen Bonding Interaction Involving

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Unstable, Meta-stable or Stable Halogen Bonding Interaction Involving Negatively Charged Donors? A Statistical and Computational Chemistry Study Zhuo Yang, Zhijian Xu, Yingtao Liu, Jinan Wang, Jiye Shi, Kaixian Chen, and Weiliang Zhu J. Phys. Chem. B, Just Accepted Manuscript • Publication Date (Web): 12 Nov 2014 Downloaded from http://pubs.acs.org on November 13, 2014

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The Journal of Physical Chemistry

Unstable, Meta-stable or Stable Halogen Bonding Interaction Involving Negatively Charged Donors? A Statistical and Computational Chemistry Study Zhuo Yang, †, 1 Zhijian Xu, †,‡, 1 Yingtao Liu, † Jinan Wang, † Jiye Shi, †

†

§,*

Kaixian Chen,

and Weiliang Zhu †, *

Drug Discovery and Design Center, Key Laboratory of Receptor Research, State Key

Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China ‡

State Key Laboratory of Medicinal Chemical Biology, Nankai University

§

Informatics Department, UCB Pharma, 216 Bath Road, Slough SL1 4EN, United

Kingdom 1

These authors contributed equally to the work.

*

To whom correspondence should be addressed. Phone: +86-21-50805020, Fax:

+86-21-50807088, E-mail: [email protected], [email protected].

ACS Paragon Plus Environment


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ABSTRACT The non-covalent halogen bonding could be attributed to the attraction between the positively charged σ-hole and a nucleophile. Quantum mechanics (QM) calculation indicated that the negatively charged organohalogens have no positively charged σ-hole on their molecular surface, leading to a postulation of repulsion between negatively charged organohalogens and nucleophile in vaccum. However, PDB survey revealed that 24% of the ligands with halogen bonding geometry could be negatively charged. Moreover, 36% of ionizable drugs in CMC (Comprehensive Medicinal Chemistry) are possibly negatively charged at pH 7.0. QM energy scan showed that the negatively charged halogen bonding is probably meta-stable in the vacuum. However, the QM calculated bonding energy turned negative in various solvents, suggesting that halogen bonding with negatively charged donors should be stable in reality. Indeed, QM/MM calculation on three crystal structures with negatively charged ligands revealed that the negatively charged halogen bonding was stable. Hence, we concluded that halogen bonding with negatively charged donors is unstable or meta-stable in the vacuum but stable in protein environment, and possesses similar geometric and energetic characteristics as conventional halogen bonding. Therefore, negatively charged organohalogens are still effective halogen bonding donors for medicinal chemistry and other applications.

KEYWORDS: Halogen bonding, Negatively charged organohalogens, Negatively charged halogen bonding, QM/MM


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INTRODUCTION

Covalent-bonded halogens, especially heavy halogens (i.e. C–X, X = Cl, Br or I), display a positive electrostatic region along the extension of the covalent-bond, which is called the σ-hole; while the electrostatic potentials on the ring region perpendicular to the bond are usually negative.1-9 This anisotropy of charge distribution of halogen atoms has drawn much attention during past decades.7,

10-23

The non-covalent

attractive interaction between the σ-hole of halogen atoms and a nucleophile (i.e. Lewis base), viz. halogen bond (XB) has already shown practical value in a variety of fields, including crystal engineering,4,

6, 8, 11

polymer chemistry,10,

12, 24

inorganic

chemistry,4-6, 11 etc.

In medicinal chemistry, halogenation is one of the most common methods of molecular modification.25-28 In addition to traditional optimizations of molecules in the aspects of physical chemistry properties, e.g. increasing membrane permeability, facilitating the blood-brain barrier crossing and prolonging the lifetime of the drug, the introduction of heavy halogen atoms into drug molecules could also increase binding affinity remarkably by forming halogen bonds with target proteins analogous to hydrogen bond.15, 29-30

Studies have already shown the important role of halogen

bonding in hit identification and lead optimization, e.g. phosphodiesterase type 5 (PDE5) inhibitors,31 human Cathepsin L (hCatL) inhibitors, nicotinic acetylcholine receptor (nAChR) agonist,32 etc. Very recently, it was found that halogen bonds could contribute

to

the

binding

between

organohalogens and


plasma

transport


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proteins/cytochrome P450/Glutathione S-transferases, indicating the contributions of halogen bonding to tuning ligand ADME/T property.33

To improve the binding affinity, highly electronegative or positively charged groups/moieties, e.g., nitro group or fluorine atom, could be introduced into oranohalogens to improve the electropositivity of the σ-hole.34 In addition, negatively charged acceptor could further enhance the halogen bonding strength.9, 35 For instance, the magnitude of the halogen bond C6F5I…Cl- can be as much as -23.80 kcal/mol (at MP2/aug-cc-pVDZ level).35 Nevertheless, most of the abovementioned studies only involved neutral organohalogens as halogen bonding donors.

In reality organohalogens including some drug molecules, could also be negatively charged. To the best of our knowledge, there is no systematic study about the interaction between a negatively charged organohalogen and heavy atoms like nitrogen and oxygen (called negative halogen bonding hereinafter). In particular, for the halogen bonding donors that deprotonate at physiological pH value, how would the negative net charge affect the normally positively charged σ-hole of the halogen atoms? Would the σ-hole still retain? Would these negatively charged molecules still form attractive interactions with nucleophiles? How prevalent is this type of interaction in PDB? Hence, it is of significance to perform a systematic study to explore the prevalence of the negatively charged molecules as halogen bonding donors and their effects on halogen bonding strength.

Here, we performed a study aiming to explore the potential effects of the


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negatively charged donors on halogen bonding through the combined use of database survey, quantum mechanics and quantum mechanics/molecular mechanics (QM/MM) calculations. The survey revealed that the charged molecules accounted for more than half of the totality not only of the organohalogens in CMC, but also of the ligands that display halogen bonding geometry in the PDB. QM/MM calculations along with quantum mechanics-based energy scan revealed the similarities and differences between the typical halogen bonding and that with negatively charged donors, which could be of great value to further applications of halogen bonding in drug design and discovery.

MATERIALS AND METHODS

ESP on a molecular surface.

The electrostatic potential (ESP) V(r) around a

molecule can be calculated rigorously by, = ∑ |

− |

′ ′ ′

,

(1)

where ZA is the charge on nucleus A, located at RA, and ρ(r) is the molecule’s electronic density. V(r) is a physical observable which can be determined both experimentally using diffraction techniques, and computationally. Its sign in any region of space depends upon whether the positive contribution of the nuclei or the negative contribution of the electrons is dominant. When plotted on the surface of a molecule (electron density ρ = 0.001 au) ,36 V(r) is designated VS(r) and its local most positive and most negative values (of which there may be several) are identified as VS,max and VS,min. In this study, VS(r), VS,max and VS,min were calculated by Multiwfn



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(version: 3.2) .37

Database survey for negatively charged organohalogens. The CMC and the PDB were applied for the statistical analysis of negatively charged halogenated molecules at physiological pH value. The CMC is updated by Accelrys annually with compounds appearing in the United States Approved Names (USAN) list for the first time (1900 ~ present), thus covers most of the launched drugs. The 9,288 compounds in the CMC (version 2011.2) were exported in sdf format. Inorganic salts and very large molecules (molecular weight > 1000) were stripped off using Pipeline Pilot 7.5.30 After the remaining compounds were converted into three-dimensional structures in mol2 format by SYBYL 6.8,29 the Epik module34, 38-39 in Schrödinger 2010 software suite was applied to predict the protonation status at pH 7.0.

Crystal structures with two types of halogen bonds in the PDB were surveyed: C−X···Y and C−X···π (Figure 1).26, 40-42 For C−X···Y halogen bond, Y represents O, N or S with the intermolecular X···Y distances shorter than the sums of vdW radii (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 larger than 140°.26 For C−X···π halogen bond, π systems from aromatic residues (Phe, Tyr, His, and Trp) were considered when they satisfy the following criteria: d(Cl⋅⋅⋅π) < 4.2 Å, d(Br⋅⋅⋅π) < 4.3 Å, d(I⋅⋅⋅π) < 4.5 Å, α < 60° and θ > 120°.26 All the small molecules forming halogen bonds with proteins were exported in sdf format without hydrogen atoms. The LigPrep module40 in


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Schrödinger 2010 software suite was then applied to add hydrogen atoms and to predict the protonation status at pH 7.0.

Figure 1. Two types of halogen bonds in PDB, viz. (a) C−X···Y and (b) C−X···π. QM/MM calculation. To explore the possible halogen bonds between negatively charged organohalogens and proteins, a two-layer ONIOM (our own N-layered integrated molecular orbital and molecular mechanics) method43-45 was adopted for the QM/MM calculation of halogen bonds in the crystal structures. 3N5J,46 1P5E47 and 3JZB48 were selected as model systems with negatively charged molecules containing Cl, Br and I, respectively.

The ligands in the three crystal structures were predicted to be deprotonated by LigPrep and PROPKA (version: 3.1)49-52 at the pH values of the crystallization (Tables S1 & S2, Supporting Information). Only the protein monomers which form halogen bonds with the ligands were kept for the QM/MM calculations. The pKa values of ionizable residues in the proteins were calculated by H++ website42, 53-55 at the pH values of the crystallization and hydrogen atoms were added accordingly. The ligands and the corresponding protein backbones that form halogen bonds were



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included in the QM region (Figure 4) which was described at the M06-2X/LanL2DZ level of density functional theory (DFT) for 3JZB and at the M06-2X/6-311++G** level for 3N5J and 1P5E.33 The rest part of the proteins was treated as the MM layer of the system and described by the AMBER parm96 force field.56

The QM/MM optimization was carried out without any constrains in the vacuum. The QM layer of the model was then extracted for single-point energy calculation at the MP2/aug-cc-pVDZ level, while Stuttgart/Dresden pseudopotential (SDD) basis set was adopted for iodine atoms in 3JZB.31, 57-59 The binding energies between the ligands and the protein backbones were assessed from equation (2).

∆ = − + +

(2)

where ∆E is the binding energy, Ecom is the energy of the complex, Edonor and Eacpt are the energies of the donor and the acceptor molecule, respectively, and BSSE stands for the basis set superposition error corrections.60 All these calculations were carried out with Gaussian 09 suite of programs.61

Quantum Mechanics-Based Grid Scan. The halogen bond distance and angle can be described distinctly by quantum mechanics-based grid scan from the aspect of interaction energy. The model molecules chosen as the halogen bond donors are electric neutral halobenzenes (phX, X = Cl, Br, I) and 4-halo-benzoic acids (p-CO2--phX, X = Cl, Br, I), which are electronegative at physiological pH value; the acceptor molecule is N-methylacetamide (BB) in order to mimic the protein backbone.23


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The geometry of every model complex was fully optimized with the acceptor atom (carbonyl oxygen) restricted in the plane of benzene and the plane of BB perpendicular to that of benzene (Figure S1) at the M06-2X level of theory,62 which has been reported to give good performance on the optimization of the halogen bond complexes.9, 26, 62-65 The SDD basis set was employed for iodine, whereas for other atoms aug-cc-pVDZ was applied.57, 59 Based on the optimized geometry, the halogen bond distance (d(X···O)) was scanned every 0.1 Å from 2.9 Å to 4.0 Å, and every 0.5 Å between 4.0 Å and 10.0 Å; meanwhile, the halogen bond angle (∠(C-X···O)) was scanned every 5° from 120° to 180°. Single-point energy calculations of the complex and each monomer were carried out at every point of grid, and the interaction energies including basis set superposition error (BSSE) corrections were assessed from equation (2). The grid scan in different solvents was carried out using the conductor-like polarizable continuum model (CPCM).66 The interaction energies evaluated in solvent was assessed from equation " " " ∆ = ! − _$! + !_$!

(3)

Superscript S represents energy with solvent effect. Subscript A_bAB means energy of monomer A calculated with the whole basis functions of dimer AB, where atoms of monomer B were treated as ghost atoms. In this way, we can obtain the BSSE corrected interaction energy with solvent effect. All these calculations were carried out with Gaussian 09 suite of programs. RESULTS AND DISCUSSION



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ESP of neutral and negatively charged organohalogens. In order to explore the potential effect of the negative charge on the σ-hole of halogen atoms, VS,max values of the halogen atoms were calculated in vacuum(Figure 2).

Figure 2. Electrostatic potentials mapped on the molecular surface (electron density ρ = 0.001 au) of (a) halogenobenzenes; (b) 4-fluo-halogenobenzenes; (c) 4-halo-anilines; (d) 4-halo-benzoic acids; (e) 4-halo-benzoates. As

expected,

for

neutral

organohalogens

(phX,

X

=

Cl,

Br,

I),

electron-withdrawing groups such as fluorine atom (p-F-phX, X = Cl, Br, I) or carboxyl group (p-CO2H-phX, X = Cl, Br, I) enhance the σ-hole (Figures 2b & d), resulting a more positive VS,max (Table 1); while electron-donating groups, e.g. the amino group (p-NH2-phX, X = Cl, Br, I), induce a smaller σ-hole (Figure 2c) and a less positive VS,max (Table 1). However, when the 4-halobenzoic acids are deprotonated (p-CO2--phX, X = Cl, Br, I), the electrostatic potentials all over the molecular surface turn negative. In other words, there is no conventional positively charged σ-hole existing on halogen atoms.


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The corresponding VS,max values were negative (Table 2), indicating possible repulsive X···Y/π interactions. However, the calculated potentials also show that the region of previous σ-hole displays less negative electrostatic potentials than other region with the order Cl < Br < I (Figure 2e & Table 2)

The interaction energy of neutral and negative halogen bonding. The correlation of ∆E with the VS,max of the halogen σ-hole has been demonstrated multiple times.6, 8-9 So the negative VS,max of the halogen σ-hole of deprotonated 4-halobenzoic acids suggested a positive interaction energy. To verify this inference, quantum chemistry optimization of halogen bonding complexes of the organohalogens with ammonia (NH3) as the acceptor were carried out in the vacuum; the interaction energies (∆E) of optimized complexes were then calculated (Tables 1 & 2).

For the neutral halogen bonding complexes, all the optimizations terminated in a typical halogen bonding geometry and most of them displayed an optimal linear interaction except for the p-NH2-phCl···NH3 (Table 1). The hydrogen atoms of ammonia in the optimized complex of p-NH2-phCl···NH3 have short interaction distances to chlorine (Figure S2), thus could interact with the chlorine, resulting a more negative interaction energy, although the VS,max the σ-hole on the chlorine is almost zero. Apart from this complex, other linear complexes do show a good correlation (R2 = 0.95) of ∆E with the VS,max of the halogen σ-hole (Figure S3).

Table 1. The VS,max on halogen atoms, geometrical parameters and interaction energy



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(∆E) of optimized model organohalogens with NH3. phX p-F-phX X VS,maxa

Dopt

b

Aopt

c

d

∆E

VS,max Dopt

Aopt

p-NH2-phX VS,max Dopt

∆E

Aopt

∆E

Cl

4.33

3.14 180.0 -0.78

6.72

3.13 178.4 -1.00

0.58

3.17 160.7 -0.90

Br

8.36

3.13 179.6 -1.82

10.84 3.12 179.7 -2.08

4.74

3.15 179.7 -1.50

I

19.98

3.14 179.9 -3.59

22.53 3.11 179.9 -3.96

16.50 3.16 179.7 -3.25

a

b

c

Values are in kcal/mol. Values are in angstrom. Values are in degree. d Values are in kcal/mol. For the negative halogen bonding system in the vacuum, the optimization of 4-bromobenzoate and 4-chlorobenzoate with NH3 could not end in a halogen bonding geometry, suggesting that the negative halogen bonding between ammonia and 4-bromobenzoate or 4-chlorobenzoate is unstable. This result is expected and is in agreement with the calculated negative VS,max of the halogen σ-holes. However, 4-iodobenzoate could form a weak attractive halogen bonding interaction with NH3, which may be on account of the strong polarizability of the iodine atom, although the VS,max of the iodine atom was also negative. For the unstable halogen bonding, single point energy calculation with fixed geometry (viz. d(X···N) = 3.2 Å and ∠C–X···N = 180°) resulted in a positive energy, implying again a repulsive interaction (Table 2). Accordingly, the interaction involving negatively charged donors seems to be unstable in the vacuum. Table 2. The VS,max on halogen atoms, geometrical parameters and interaction energy (∆E) of optimized 4-halo-benzoic acids with NH3 in different protonation states. p-CO2--phX p-CO2H-phX X VS,maxa Doptb Aoptc ∆Ed VS,max Dopt Aopt ∆E e Cl 8.85 3.12 178.5 -1.23 -48.06 1.73f

a

Br

12.73

3.11

179.8

-2.31

-43.79

-

-

1.02f

I

24.30

3.10

179.8

-4.20

-32.84

3.30

179.9

-0.31

b

c

d

Values are in kcal/mol. Values are in angstrom. Values are in degree. Values are


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in kcal/mol. e Optimization could not terminate in a typical halogen bonding geometry. f Single point energy interacting with NH3 when d(X···N) = 3.2 Å and ∠C–X···N = 180°. Halogenated drugs with negative charges. To investigate how prevalent the negatively charged molecules with heavy halogens are in drugs, the CMC database was surveyed.

Out of the 9,288 compounds, 8,714 are chemical drugs, in which 2,263 contain halogen atoms (F, Cl, Br and I) and 1,571 can act as halogen bond donors (Figure 3a, Table S3). At pH 7.0, only 43% molecules in the CMC retained neutral, whlie 51% molecules with heavy halogen atoms are charged. Among the ionizable drugs with heavy halogen atoms, 36% are negatively charged. Therefore, the potential interaction between the negatively charged organohalogen drugs and their target, namely negative halogen bonding, is of significance for understanding drug-target interactions.

Figure 3. Proportions of organohalogens at different charge states in (a) the CMC and (b) the PDB with potential halogen bonding interaction.



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Searching for negative halogen bonding in PDB. The PDB was surveyed to validate the potential halogen bonding between negatively charged organohalogens and biomacromolecules. The current PDB (April 2014 release) contains 4,913 complex structures in which ligands are halogenated, among which 2,893 structures contain heavy organohalogens. Filtering these structures by the halogen geometry criteria resulted in 1,498 halogen bonds presented in 907 structures which corresponding to 1,322 small molecules (Table S4).

As we discussed previously, negatively charged organohalogens could barely form an attractive interaction as a halogen bonding donor in the vacuum. Noticeably, 24%

of

the

1,322

ligands

showing

halogen

bonding

geometry

with

biomacromolecules would deprotonate at pH7.0, resulting in negative net charge (Figure 3b and Table S4). This observation suggests that the negative halogen bonding geometry is prevalent in the PDB. In addition, a detailed analysis revealed that there are 3 ~ 10 intervening atoms (topology distance) between the halogen and the anionic oxygen in PDB, with a peak at 5 intervening atoms. The corresponding physical distances are 3.6 ~ 8 Å, with a peak at 6 ~ 8 Å (Figure S4). QM/MM calculations were then carried out to investigate whether these negative halogen bonding interactions in crystals are attractive and whether they contribute to the binding affinity of drug to target.

QM/MM calculation of the negative halogen bonding energy. 3N5J, 1P5E and 3JZB were selected as model systems for halogen bonding involved with negatively


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charged ligands containing Cl, Br and I, respectively. The model systems with at most 5 intervening atoms between the halogen and the anionic oxygen and a physical distance of ~6 Å thus represent the most frequent situation of the ligands in the PDB survey (Figure S4). Superposition of the heavy atoms in the QM layer in the crystal structures and the QM/MM optimized structures resulted in RMSDs of 1.45 Å, 0.74 Å and 0.88 Å for 3N5J, 1P5E and 3JZB, respectively (Figure 4). The deviations of X···O distances of the halogen bonds between crystal and optimized structures were less than 0.1 Å, and the deviations of C–X···O angles were less than 10° (Table 3), indicating that the results of the QM/MM optimization were reliable.

Figure 4. Optimized structures of the full models at the ONIOM level for (a) 3N5J (M06-2X/6-311++G**); (b) 1P5E (M06-2X/6-311++G**) and (c) 3JZB (M06-2X/LanL2DZ). Atoms in the QM layer are presented as balls and sticks with carbon atoms in yellow for ligands and gray for proteins; hydrogen atoms in white, oxygen atoms in red, nitrogen atoms in blue, chloride atoms in green, bromine atoms in brown and iodine atoms in purple. Atoms in the MM layer are shown as cartoon. As for the 3 deprotonated ligands, the calculated ESP mapped on the whole molecular surface (electron density ρ = 0.001) are negative (Figure 5), which is similar to the model systems in the vacuum (Figure 2e). ESP is also less negative on the surface around the conventional σ-hole region.



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Figure 5. Electrostatic potentials mapped on the molecular surface (electron density ρ = 0.001 au) of ligands: (a) 3N5J, (b) 1P5E and (c) 3JZB. Table 3. Geometrical parameters of halogen bonds in the model systems in crystal and QM/MM optimized structures. Crystal Structure QM/MM Optimized Structure X PDB Acceptor ID Atom d(X···O) (Å) ∠C–X···O (°) d(X···O) (Å) ∠C–X···O (°) Cl

3N5J

O(Ser205)

2.95

164.4

3.02

159.1

Br

1P5E

O(Glu81) O(Leu83)

3.01 2.90

168.5 164.7

2.99 2.82

166.5 171.3

3JZB O(Phe218)

3.22

169.6

3.12

173.5

I

Different from the model systems (Table 2), the X···O distances and C–X···O angles in the three QM/MM optimized negative halogen bonding structures are around 2.8 ~ 3.1 Å and 159~174˚, representing a typical halogen bonding geometry in comparison with conventional halogen bonding. Therefore, the negative halogen bonding in crystal structures might be attractive interaction. Indeed, the interaction


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energies between the halogen donor and acceptor in the QM layer calculated in the vacuum are 2.65 kcal/mol, -1.09 kcal/mol and -0.58 kcal/mol for 3N5J, 1P5E and 3JZB, respectively (Table 4). The positive binding energy of the chlorinated ligand and the protein backbone, as well as no VS,max on the chlorine atom of the ligand when ESPs were calculated with three positively charged amino acids (Lys57, Arg60 and Lys257) in the vicinity (Figure S5) in 3N5J, implies a probably repulsive interaction between

the chlorine and the oxygen atom. Although the negative binding energies for other two systems (1P5E and 3JZB) suggest an attractive binding, the strength is obviously weak in comparison with -2 ~ -4 kcal/mol between electrostatically neutral halogenated ligand and protein residues. 6, 9, 13, 26, 31 Nevertheless, the negative halogen bonding is possible to be attractive, which is different from our previous understanding and results calculated from the model systems in the vacuum (Table 2), suggesting that the environment may have significant effect on the negative halogen bonding interaction. Table 4. Interaction energies of QM layer in QM/MM optimized structures of the model systems in the vacuum, chloroform (ε = 4.71), acetone (ε = 20.49) and water (ε = 78.36). QM/MM Optimized Structure PDB Acceptor X ID Atom ∆Evacuum ∆Echloroform ∆Eacetone ∆Ewater Cl

3N5J

O(Ser205)

2.67

-0.023

-0.74

-0.91

Br

1P5E

O(Glu81) O(Leu83)

-1.09

-4.09

-4.95

-5.15

I

3JZB

O(Phe218)

-0.58

-2.69

-3.34

-3.50

The effect of dielectric constant on the negative halogen bonding. The local



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dielectric of the protein binding site around ligands is inhomogeneous.67-68 In calculations, the dielectric properties of the protein and solvent phase are represented in terms of dielectric constant (ε).69 In general, the dielectric constant can be as little as 4~5 in the protein interior and as high as approximately 80 in the vicinity of the protein surface.67-71 For the above three model systems, the ligand in 3JZB is completely buried in the protein, while ligands in the other two are located in the binding sites accessible to water molecules. We calculated the interaction energies of the optimized QM layer in various solvents with different dielectric constant, viz., chloroform (ε = 4.71), acetone (ε = 20.49) and water (ε = 78.36), respectively (Table 4). Interestingly, the calculated binding energies are all negative for the 3 systems, indicating that the negative halogen bonding are attractive in all the 3 solvents. Surprisingly, it is observed that the binding energies grow stronger as the dielectric constant increases (Table 4), suggesting that negative halogen bonding is stable in the real biological environment.

Halogen bonding interaction energy versus dielectric constants. To further investigate the characteristics of the negative halogen bonding, we performed quantum mechanics-based energy scans in the vacuum and in different solvents using the complexes formed by neutral or negatively charged organohalogens and N-methylacetamide (BB) as model systems. Figure 6 depicts the scanned energy landscapes in the vacuum, demonstrating that neutral halogen bonding systems (halobenzene-BB complexes) have apparent negative energy well with strongest binding energy of -1.36, -2.44 and -4.12 kcal/mol for chlorobenzene-, bromobenzene-


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and iodobenzene-BB systems, respectively (Fiugres 6a-c & Tables S5-7 in Supporting Information). Differently, although the scanned interaction energy profiles of the three negative halogen bonding systems (halobenzonate-BB complexes) are very similar in shape to those of the neutral systems, the lowest binding energy are +1.57, +0.81 and -0.34 kcal/mol for 4-chlorobenzoate-, 4-bromobenzoate- and 4-iodobenzoate-BB systems, respectively (Figures 6d-f & Tables S8-10), demonstrating that 4-chlorobenzoate- and 4-bromobenzoate-BB interactions are always repulsive at all the scanned angles and distances, while 4-iodobenzoate-BB interaction could be attractive when the interaction distance is around 3.3±0.2 Å and the angle around 180±10˚. Scans of the interaction energy for the halobenzonate-ammonia model systems in the vacuum resulted in similar interaction energy landscapes, with the lowest binding energy +1.56, +0.88 and -0.31 kcal/mol for 4-chlorobenzoate-, 4-bromobenzoate- and 4-iodobenzoate-NH3 systems, respectively (Tables S11-13 in Supporting Information). Nevertheless, the scanned interaction energy profiles for the negative halogen bonding systems reveal the existence of energy well with interaction distance of 3.3±0.2 Å and angle 180˚, suggesting that meta-stable structures do exist for the negative halogen bonding systems.



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Figure 6. Illustration of grid-scans of interaction energies in the vacuum between (a) chlorobenzene (phCl); (b) bromobenzene (phBr); (c) iodobenzene (phI); (d) 4-chlorobenzoate (p-CO2--phCl); (e) 4-bromobenzoate (p-CO2--phBr); (f) 4-iodobenzoate (p-CO2--phI) and N-methylacetamide (BB) with the change in X···O distance and C–X···O angle. As 180° is the optimal angel of ∠ (C-X···Y) for interaction between BB and phX or p-CO2--phX in the vacuum, the interaction distance was further scanned to 10 Å for bromobenzene- and 4-bromobenzoate-BB systems. Figure 7 shows both systems do have apparent energy wells, but of different profiles. The energy wells have different depth (Figures 7b & d); the former is about 2.5 kcal/mol while the later about 0.7 kcal/mol. When the distance exceeds the optimal value, the energy of the neutral halogen bonding interaction goes uphill all the way until reaching a plateau (Figure 7b). On the contrary, an energy barrier is observed in the negative halogen bonding system (Figure 7d), suggesting that the interaction at 3.2 Å and 180° is a local minimum, thus, which corresponds to a meta-stable structure.


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Figure 7. Illustration of grid-scan of interaction energies between (a) bromobenzene (phBr); (c) 4-bromobenzoate (p-CO2--phBr) and N-methylacetamide (BB) with the change in Br···O distance and C–Br···O angle. Curves of interaction energies between (b) bromobenzene (phBr); (d) 4-bromobenzoate (p-CO2--phBr) and N-methylacetamide (BB) with Br···O distance varying from 2.9 to 10.0 Å when C–Br···O angle fixed to 180°. Figure 8 illustrates the scanned interaction energy of the negative halogen bonding system in different environments using 4-bromobenzoate-BB as a model system. Interestingly, the meta-stable complex turns out to be stabilized in various solvents according to the calculated negative interaction energies. The optimal distance determined by the grid scan reduces from 3.2 Å in the vacuum to 3.1 Å for all the scan models with different solvents. With the increase of dielectric constant of the solvent, the lowest interaction energy for each scan model decreases (Figure 8, 9; Table S9, S14-S18), indicating that the negative halogen bonding is more stable in the



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more polar environment. Indeed, proteins could provide an inhomogeneous polar environment to stabilize the negative halogen bonding.

Figure 8. Illustration of grid-scans of interaction energies between 4-bromobenzoate (p-CO2--phBr) and N-methylacetamide (BB) with the change in Br···O distance and C–Br···O angle in (a) the vacuum; (b) chloroform (ε = 4.71); (c) acetone (ε = 20.49); (d) methanol (ε = 32.61); (e) DMSO (ε = 46.83) and (f) water (ε = 78.36).

The above results of grid-scans may shed some lights on the negative halogen bonding. Although the σ-hole with negative potentials repulses the carbonyl oxygen of protein backbones, the interaction energy finds its local minimum at the typical halogen bonding geometry even in the vacuum. As the dielectric constant increases, the binding energies decrease to negative values for both QM/MM high layers and grid-scanned models, implying that the interactions become attractive and stable, which accounts for the result of our PDB survey.


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Figure 9. Interaction energies between 4-bromobenzoate (p-CO2--phBr) and N-methylacetamide (BB) with Br···O distance varying from 2.9Å to 10.0 Å when C–Br···O angle fixed to 180° in (a) the vacuum; (b) chloroform (ε = 4.71); (c) acetone (ε = 20.49); (d) methanol (ε = 32.61); (e) DMSO (ε = 46.83) and (f) water (ε = 78.36).

CONCLUSION

Molecules have different protonation states depending on their pKa and the pH value of the environment. Heavy-halogenated drugs that would deprotonate at the physiological pH value may display negative electrostatic potentials all over the molecular surface, but the previous electrostatically positive σ-hole of the halogen atom still presents less negative electrostatic potentials than that of the vicinity. The PDB survey demonstrates that negatively charged molecules could exhibit halogen bonding geometry similar to those electrostatically neutral molecules, which was supported by the QM/MM optimization results for three crystal structures (PDB ID: 3N5J, 1P5E and 3JZB). However, the interaction energies between the halogen-bonding donors and acceptors in the vacuum are higher than that of normal halogen bonding complex; the interactions could even become repulsive.



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Quantum mechanics-based energy scan reveals that the interaction between an electrostatically negative donor and a normal acceptor with typical halogen bonding geometry is repulsive in the vacuum but with an energy well. When solvent models are applied, the interaction energies turn negative and the energy surfaces become similar to that of a conventional halogen bonding complex.

Charged drugs are common according to the CMC survey. Our study here demonstrates that, similar to electrostatically neutral molecules, negatively charged molecules with heavy halogen atoms can also form halogen bonds, which affirms the significant role of halogen bonding in drug discovery and development.

In addition, the grid-scan results also demonstrate that the interaction energy of halogen bonding between a negatively charged donor and a normal acceptor at the optimal point decreases with increasing dielectric constant. The similar phenomenon was observed by Zhang etc. on the arginine−arginine (Arg-Arg) pairing.72 Whether the solvation effects and electrostatic energies contribute significantly to the stability of halogen bonding involving negatively charged donors in the way similar as their roles in Arg-Arg pairing requires further investigation.

Supporting Information Available: Illustration of quantum mechanics-based scan. Optimized structures of non-linear and linear halogen-bonding complexes. Plot of interaction energies (∆E) with VS,max of halogen σ-hole for halogen-bonding complexes. Calculated pKa value and details of the ligand in the protein environment by PROPKA. Frequency of the topology distances and corresponding physical


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distances between the halogen and the anionic oxygen of the ligand that halogen bonding with proteins in PDB. VS,max and VS,min of the ligand with positive charged animo acids in the vicinity (Lys57, Arg60 and Lys257) in QM/MM optimized structure of 3N5J. Organohalogens with different charged states in CMC. Organohalogens with different charged states that form halogen bonds with biomacromolecules in PDB (Protein Data Bank). Grid-scan of interaction energies (kcal/mol) between halobenzene (phX, X = Cl, Br, I) and N-methylacetamide (BB) with the change in X··O distance (A) and C–X···O angle (°) in the vacuum. Grid-scan of interaction energies (kcal/mol) between 4-halo-benzoate (p-CO2--phX, X = Cl, Br, I) and N-methylacetamide (BB) with the change in X···O distance (A) and C–X···O angle (°) in the vacuum. Grid-scan of interaction energies (kcal/mol) between 4-halo-benzoate(p-CO2--phX, X = Cl, Br, I) and ammonia (NH3) with the change in X···N distance (A) and C–X···N angle (°) in the vacuum. Grid-scan of interaction energies (kcal/mol) between 4-bromobenzoate (p-CO2--phBr) and N-methylacetamide (BB) with the change in Br···O distance (A) and C–Br···O angle (°) in chloroform (ε = 4.71), acetone (ε = 20.49), methanol (ε = 32.61), DMSO (ε = 46.83) and water (ε = 78.36). The material is available free of charge via the Internet at http://pubs.acs.org.

ACKNOWLEDGMENT

This work was supported by NNSF (81273435 and 81302699), National Science & Technology Major Project (2013ZX09103001-001 and 2012ZX09301-001-004), Ministry of Science and Technology (2012AA01A305 and 2012AA020302) and the



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State Key Laboratory of Medicinal Chemical Biology, Nankai University (20130265).

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The TOC graphic 177x63mm (300 x 300 DPI)


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Figure 1. Two types of halogen bonds in PDB, viz. (a) C-X•••Y and (b) C-X•••π. 177x139mm (300 x 300 DPI)



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Figure 2. Electrostatic potentials mapped on the molecular surface (electron density ρ = 0.001 au) of (a) halogenobenzenes; (b) 4-fluo-halogenobenzenes; (c) 4-halo-anilines; (d) 4-halo-benzoic acids; (e) 4-halobenzoates 220x114mm (300 x 300 DPI)


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Figure 3. Proportions of organohalogens at different charge states in (a) the CMC and (b) the PDB with potential halogen bonding interaction. 254x190mm (300 x 300 DPI)



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Figure 4. Optimized structures of the full models at the ONIOM level for (a) 3N5J (M06-2X/6-311++G**); (b) 1P5E (M06-2X/6-311++G**) and (c) 3JZB (M06-2X/LanL2DZ). Atoms in the QM layer are presented as balls and sticks with carbon atoms in yellow for ligands and gray for proteins; hydrogen atoms in white, oxygen atoms in red, nitrogen atoms in blue, chloride atoms in green, bromine atoms in brown and iodine atoms in purple. Atoms in the MM layer are shown as cartoon. 254x67mm (300 x 300 DPI)


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Figure 5. Electrostatic potentials mapped on the molecular surface (electron density ρ = 0.001 au) of ligands: (a) 3N5J, (b) 1P5E and (c) 3JZB. 169x194mm (300 x 300 DPI)



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Figure 6. Illustration of grid-scans of interaction energies in the vacuum between (a) chlorobenzene (phCl); (b) bromobenzene (phBr); (c) iodobenzene (phI); (d) 4-chlorobenzoate (p-CO2--phCl); (e) 4-bromobenzoate (p-CO2--phBr); (f) 4-iodobenzoate (p-CO2--phI) and N-methylacetamide (BB) with the change in X•••O distance and C–X•••O angle. 338x186mm (300 x 300 DPI)


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Figure 7. Illustration of grid-scan of interaction energies between (a) bromobenzene (phBr); (c) 4bromobenzoate (p-CO2--phBr) and N-methylacetamide (BB) with the change in Br•••O distance and C– Br•••O angle. Curves of interaction energies between (b) bromobenzene (phBr); (d) 4-bromobenzoate (pCO2--phBr) and N-methylacetamide (BB) with Br•••O distance varying from 2.9 to 10.0 Å when C–Br•••O angle fixed to 180°. 169x135mm (300 x 300 DPI)



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Figure 8. Illustration of grid-scans of interaction energies between 4-bromobenzoate (p-CO2--phBr) and Nmethylacetamide (BB) with the change in Br•••O distance and C–Br•••O angle in (a) the vacuum; (b) chloroform (ε = 4.71); (c) acetone (ε = 20.49); (d) methanol (ε = 32.61); (e) DMSO (ε = 46.83) and (f) water (ε = 78.36). 338x186mm (300 x 300 DPI)


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Figure 9. Interaction energies between 4-bromobenzoate (p-CO2--phBr) and N-methylacetamide (BB) with Br•••O distance varying from 2.9Å to 10.0 Å when C–Br•••O angle fixed to 180° in (a) the vacuum; (b) chloroform (ε = 4.71); (c) acetone (ε = 20.49); (d) methanol (ε = 32.61); (e) DMSO (ε = 46.83) and (f) water (ε = 78.36). 152x84mm (300 x 300 DPI)


Unstable, Metastable, or Stable Halogen Bonding Interaction Involving

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