Sensing Ability of Hybrid Cyclic Nanopeptides Based on Thiourea

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Sensing Ability of Hybrid Cyclic Nanopeptides Based on Thiourea Cryptands for Different Ions, A Joint DFT-D3/MD Study Mohammad Izadyar, Mohammad Khavani, and Mohammad Reza Housaindokht J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.6b09738 • Publication Date (Web): 19 Dec 2016 Downloaded from http://pubs.acs.org on December 21, 2016

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Sensing Ability of Hybrid Cyclic Nanopeptides Based on Thiourea Cryptands for Different Ions, A Joint DFT-D3/MD Study Mohammad Izadyar*, Mohammad Khavani, Mohammad Reza Housaindokht Department of Chemistry, Faculty of Sciences, Ferdowsi University of Mashhad, Mashhad, Iran [email protected] Tel/fax: +985138795457

Abstract Theoretical studies, including quantum chemistry (QM) calculations and 25 ns molecular dynamic (MD) simulations, were performed on two types of hybrid cyclic nanopeptides (HCNPs) which are constructed of tren-capped cryptand (HCNP1) and 1,3,5-triethylbenzene-capped cryptand (HCNP2) for selective complex formation with OAC‒, NO3‒, HSO4‒, F‒, Br‒, and Cl‒ ions in the gas phase and DMSO. Obtained data by M05-2X, M05-2X-D3, B3LYP and B3LYP-D3 functionals indicated that HCNPs form a stable complex with F‒ in comparison to other ions. DFT-D3 results and quantum theory of atoms in molecules (QTAIM) analysis indicated that dispersion and electrostatic interactions are the most important driving forces in HCNPs-ion complex formation, respectively. Moreover, HOMO-LUMO analysis reveals that the reactivity of HCNP2, due to a lower band gap, is more than HCNP1. High sensing ability of the studied HCNPs 1 ACS Paragon Plus Environment

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for different ions was confirmed by Fermi level shifting of HNCPs to higher values during the complex formation. Finally, MD simulation results in DMSO are in good agreement with QM calculations and indicate that F‒forms the most stable complexes with HCNPs because of more strong electrostatic interactions.

Introduction Synthetic macrocyclic receptors are applied in biological and environmental sciences

1-3

. Today, many researchers attempt to propose and synthesize different

macrocyclic compounds, in order to form selective complexes with different ions in solution phase, especially in water. Cyclic peptides (CPs) are a class of these compounds with interesting properties for application in diverse areas such as biology, medicine, catalysis, electronic, optics, material transport and selective complex formation 4-12. Some kinds of CPs, due to self-assembling through hydrogen bonds, are able to form nanotubular structures 13. Cyclic peptide nanotubes (CPNTs), constructed by alternating D- and L-amino acid residues, are the first group of the CPNTs which have been proposed by Ghadiri and co-workers

14

. Many theoretical and

experimental studies have been performed on different materials which are composed of CPs.

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Subramanian and co-workers by employing molecular dynamic simulations, investigated the ability of CPNTs for transmission of 5-fluorouracil along the lipid bilayer 15. Their results indicated that the CPNT constructed of [-(D-Trp-L-Leu)4] has a good ability to be used as a molecular channel in a lipid bilayer. Moreover,

Granja

group

proposed

a

new

peptide

with

3-

aminocyclohexancarboxilic acid residue 16 which, not only makes a CPNT but also is of high ability of ion transport though the corresponding molecular channel. The ability of cyclic peptide to be used as a sensor for different ions has been reported in some theoretical researches 17,18. For example, Chermahini and co-workers by employing quantum chemistry calculations reported that three and four-member CPs constructed of alanine amino acid are selective sensors for Li+ in the presence of Na+, K+, Rb+ and Cs+ 17. Also, they reported the sensing ability of cyclo(L-Pro)3CP and cyclo(cis-Ala)4 for selective complex formation with Li+ and Be2+, respectively, in the presence of other alkaline earth metal ions

18

.Today, non-amino acid residues have been

applied for tuning the CPs properties 19. Because of the importance of HCNPs applications in selective ion extraction and investigation the role of dispersion interactions during the complex formation, we studied the ability of two hybrid cyclic peptides (HCNPs), composed of the


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tren-capped cryptand (HCNP1) and 1,3,5-triethylbenzene-capped cryptand (HCNP2), in order to form selective complexes with OAC‒, HSO4‒, NO3‒, Cl‒, F‒ and Br‒ ions. For this purpose, density functional theory (DFT) and DFT dispersion corrected (DFT-D3) calculations and 25 ns molecular dynamic simulations were performed in the gas phase and DMSO. The importance of this study is to predict the selective extraction power of these hybrid cyclic nanopeptides in the gas and solution phases for different ions.

Theoretical methods DFT and DFT-D3 calculations The structures of the hybrid cyclic nanopeptides (HCNPs) and their complexes with different ions (X= OAC‒, HSO4‒, NO3‒, Cl‒, F‒ and Br‒) were optimized by the DFT method at B3LYP

20

and M05-2X

21

levels and dispersion

DFT-D3 method at B3LYP-D3 and M05-2X-D3 levels 22 (D3 version of Grimme’s dispersion with the original D3 damping function, which is also called the zerodamping version) with 6-31G (d) basis set

23

in the gas phase and DMSO as the

solvent. In order to eliminate the effect of the basis set incompleteness, EBSSE as the basis set superposition error, (BSSE) correction was calculated by employing the counterpoise correction method. Minnesota density functionals such as M05-2X do 4 ACS Paragon Plus Environment


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not properly describe the London-dispersion interactions, while Grimme’s DFT-D3 functionals can solve this problem. Therefore in order to have more accurate results, M05-2X-D3 functional has been employed to cover the effects the Londondispersion interactions in our calculations 24,25. In order to have an estimation of the zero point vibrational energies (ZPVEs) and thermodynamic parameters during the complex formation, frequency calculations were performed. Since, B3LYP functional cannot describe dispersion interactions in contrast to B3LYP-D3 26, the energy difference obtained by these functionals was reported as dispersion interaction energy. All of these calculations were performed using the Gaussian 09 package 27. To investigate the electrostatic interaction between the HCNPs and different ions, natural bond orbital (NBO) analysis was performed

28

at the B3LYP-D3/6-

311++G(d,p) level of the theory. By applying NBO analysis, molecular orbital and donor-acceptor interactions in the HCNPs complexes were investigated. In order to analyze the nature and power of hydrogen and halogen bonds between the HCNPs and ions, electron localization function (ELF) orbital locator (LOL)

36,37

29-35

, localized

and quantum theory of atoms in molecules (QTAIM)

analyses were performed by MultiWFN 3.1 39.


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Molecular dynamic simulations In order to investigate the dynamical behavior of hybrid cyclic nanopeptides in DMSO, molecular dynamic (MD) simulation was performed by employing the Amber 12.0 software 40. Structural parameters of HCNPs were obtained by DFTD3 geometry optimization at the B3LYP-D3/6-31G(d) level and the atomic charges of all structures were calculated by the CHelpG method at the same level. Ten anions in a distance of 5 Å to HCNPs within ten cations of Na+ and 3 Å to each other were added around each nanopeptide, randomly. Then each system was solvated with a cubic box of DMSO so that solvent molecules were located in 15 Å to the solute molecules.

DMSO was simulated according to Fox and

Kollman parameters 41. In the first step of MD simulation, energy minimization for 30000 cycles was performed on each system. Then, in an NVT ensemble, the systems were heated from 0 to 298.15 K during 2000 ps, with 1000 kJ.mol -1.nm-2 restraining force constant for solute molecules. Obtained structures from this step were equilibrated during 2000 ps in an NPT ensemble (at 298.15 K and 1 atm) without any positional restraint. After this step, the MD simulations of the products in 25 ns were performed with all atoms general amber force field (GAFF) 42. 6 ACS Paragon Plus Environment


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In order to calculate the long range electrostatic interactions, Particle Mesh Ewald (PME) coupled periodic boundary conditions with 8 Å direct space cut-off was applied

43

. SHAKE constraints on all bonds involving hydrogen atoms was

used with a time step of 2 fs

44

. To control the temperature of the systems in the

NPT MD simulation steps, Langvin thermostat

45,46

with collision frequency of 2

ps-1 and 1 ps pressure relaxation time was used.

Results and discussion Structural and IR vibrational frequency analysis Two hybrid cyclic nanopeptides composed of the tren-capped cryptand (HCNP1) and 1,3,5-triethylbenzene-capped cryptand (HCNP2), were chosen to investigate their selective complex formation with OAC‒, HSO4‒, NO3‒, Cl‒, F‒ and Br‒ ions. Initial structures of HCNP1 and HCNP2 were obtained from X-ray crystal structures which were synthesized by Jolliffe and coworkers 47. The structures of HCNPs and HCNP-ion complexes were optimized in the gas phase and DMSO by using M05-2X, M05-2X-D3, B3LYP and B3LYP-D3 functionals. Optimized structures of HCNPs with atom numbering were shown in Figure 1. According to this figure, there are nine N―H bonds for hydrogen bond formation in each HCNP with OAC‒, HSO4‒ and NO3‒ ions and halogen bond with Cl‒, F‒ and Br‒ ions. Calculated structural parameters of HCNPs with different 7 ACS Paragon Plus Environment

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functionals are in good agreement with experimental data

47

and solvent has not

important effect on the structural parameters of HCNPs, according to Table S1.

Figure 1. Optimized structures of HCNP1, HCNP2 and different ions in the gas phase at the B3LYP-D3/6-31G(d) level.

Figure 2 shows the optimized structures of HCNP1 and HCNP2 complexes in which all ions were located in the cavity of HCNPs. Comparison of N―H bond length in the free HCNPs and complexes indicates that the N―H bond length increases due to the hydrogen and halogen bond formation between ions and N―H bonds (Table S1). Also, considering the H-bond lengths in the gas phase and DMSO indicates that solvent increases the length of H-bonds (Table S2). Based on the optimized structures there are five and nine H-bonds between OAC‒ and HSO4‒ with HCNP2, respectively, while, there are four and six H-bonds with HCNP1. Moreover, HCNP1 has four halogen bonds with Br‒ and F‒ ions, 8 ACS Paragon Plus Environment


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which, HCNP2 is formed six and five halogen bonds with these ions, respectively. These results show that HCNP2 forms more stable complexes with different ions in comparison to HCNP1.


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Figure 2. Optimized structures of HCNP1 (A) and HCNP2 (B) complexes in the gas phase at the B3LYP-D3/6-31G(d) level.

It is confirmed that DMSO increases Hydrogen and halogen bond lengths, which in turn reduces the stability of the HCNPs-X complexes. According to structural analysis, calculated distances between the ions and HCNP1 and HCNP2 are as follow: Br‒> Cl‒> NO3‒> HSO4‒> OAC‒> F‒ and Br‒> Cl‒> HSO4‒> NO3‒> OAC‒> F‒, respectively. These trends reveal that HCNPs-F- are the most stable complexes. In order to confirm hydrogen and halogen bonds formation between HCNPs and different ions, IR vibrational frequencies of N―H bonds in free HCNPs and their complexes were performed (Table S3).Table S3 indicates a noticeable redshift for N―H bonds and confirms H-bond formation. Halogen bond formation between halide ions and H atoms of HCNPs shows a significant red-shift in N―H bonds, too. Binding energy analysis Thermodynamic parameters for complex formation between different ions and hybrid cyclic nanopeptides and EBSSE were calculated by M05-2X, M05-2XD3, B3LYP and B3LYP-D3 functionals are reported in Table 1. Calculated values of the binding energy (∆E) and Gibbs free energies of complex formation (∆G) by



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B3LYP-D3 functional are greater than B3LYP, M05-2X and M05-2X-D3 which show an important contribution of dispersion forces. According to Table 1, calculated ∆E values of the HCNP2-X complexes are more than HCNP1-X ones, which indicate a more stability of the HCNP2-X structures. Moreover, ∆E and ∆G values are lower in DMSO than gas phase, showing that DMSO reduces the complex stability which is in agreement with structural analysis results. The stability trend, based on ∆E values, obtained by B3LYP-D3 functional, is as follows: F‒> Br‒> NO3‒> HSO4‒> OAC‒> Cl‒ and F‒> OAC‒> HSO4‒> NO3‒> Br‒> Cl‒ for HCNP1-X and HCNP2-X complexes, respectively. This trend confirms the most stability of the structures of HCNPs-Fcomplexes in the gas phase and DMSO. To evaluate the contribution of dispersion interaction energies (∆Edis and ∆Gdis), the differences in energies obtained by B3LYP-D3 with B3LYP and M052X with M05-2X-D3 were calculated. Dispersion interaction energy values of HCNP2-X complexes are significantly greater than HCNP1-X, which indicate a more effective role of dispersion interactions in HCNP2-X complexation. The B3LYP functional cannot describe the dispersion interaction correctly, especially not at large distances, while B3LYP-D3 includes an additional dispersion correction 22. Therefore, the calculated dispersion energies using the M05-2X and M05-2X-D3 functionals are significantly lower than the corresponding calculated 11 ACS Paragon Plus Environment

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values obtained by the B3LYP and B3LPY-D3 functionals. Based on the obtained results from different functionals, it can be concluded that DMSO as a solvent reduces the stability of the complexes, both of the HCNPs are able to form selective complexes with F‒ in the presence of other ions, HCNP2 is a better receptor for F‒ in comparison to the HCNP1 and finally, the inclusion of the dispersion interactions are important in the energetics of this type of nanostructures. Minnesota methods are very sensitive to the numerical quadrature grid.48 Johnson et al. reported that the M05-2X results, when using a dense DFT grid, on the carbohydrate compounds are in good agreement with MP2 calculations. 49 It was also concluded that the popular B3LYP results are not good for carbohydrates conformational studies, while the M05-2X functional is in agreement with MP2. Here, the obtained results indicate that ‫∆׀‬G‫ ׀‬values calculated by the M052X functional for all the complexes are more than calculated by B3LYP which shows a more stability of the HCNP complexes, in comparison to B3LYP, in both of the gas phase and DMSO. Also, the B3LYP results indicate that HSO4‒-HCNP1 complex is not thermodynamically, favorable, (∆G>0), which is in contrast to the experimental data.47 Based on the different analyses, in the case of the HCNP complexes, more reasonable data is expectable by M05-2X functional than B3LYP, from the energy point of view. 12 ACS Paragon Plus Environment


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Table 1. Thermodynamic parameters and EBSSE (kcal.mol-1) of HCNPs-X complexes in the gas phase and DMSO. M05-2X M05-2X-D3 Dispersion B3LYP B3LYP-D3 energies HCNP1 -∆G -∆E EBSSE -∆G -∆E EBSSE -∆Gdis -∆Edis -∆G -∆E EBSSE -∆G -∆E EBSSE Ion 44.99 58.05 48.58 62.20 3.59 4.15 37.04 48.79 53.51 65.08 OAC― Gas 18.44 18.50 21.52 21.96 5.40 18.90 11.11 24.07 5.71 5.17 4.35 10.47 13.85 27.88 DMSO Br― Cl― F― HSO4― NO3― Ion OAC― Br― Cl― F― HSO4― NO3―

Gas DMSO Gas DMSO Gas DMSO Gas DMSO Gas DMSO HCNP2 Gas DMSO Gas DMSO Gas DMSO Gas DMSO Gas DMSO Gas DMSO

Dispersion energies -∆Gdis -∆Edis 16.47 18.20

16.29 17.41

63.70 21.05

72.72 29.29

25.30

65.51 23.18

75.42 31.83

25.70

1.81 2.13

2.70 2.54

56.36 12.03

64.58 20.61

24.29

67.94 24.63

77.56 33.47

28.10

11.58 12.60

12.98 12.87

54.19 8.55

61.69 16.16

8.63

55.66 10.89

64.92 19.30

9.01

1.47 2.34

3.24 3.14

48.68 5.18

55.54 13.25

5.70

55.63 10.56

64.17 17.85

10.16

6.95 5.39

8.63 4.60

93.07 40.07

101.35 51.88

37.35

95.21 35.42

105.11 44.53

41.13

2.14 -4.65

3.76 -7.35

118.54 36.70

129.38 48.08

57.85

124.80 51.58

138.03 67.35

59.77

6.26 14.88

8.65 19.27

48.39 7.41

62.90 22.17

16.82

54.12 18.70

68.44 31.78

17.02

5.73 11.29

5.54 9.61

37.52 -3.94

50.16 11.57

18.09

55.24 19.50

70.09 34.67

19.62

17.72 23.44

19.93 23.10

52.74 13.57

63.15 25.45

16.66

55.48 17.71

66.85 29.29

16.97

2.74 4.14

3.70 3.84

47.55 8.61

58.08 19.66

18.28

59.21 21.59

70.62 32.43

20.81

11.66 12.99

12.54 12.77

69.51 23.28

80.78 36.19

17.66

72.08 27.22

87.20 41.81

17.68

2.57 3.94

6.42 5.62

60.15 15.19

73.02 29.05

20.15

76.51 138.10

89.66 45.52

21.65

16.36 122.92

16.64 16.47

67.44 18.87

72.88 26.55

17.10

67.58 21.14

75.37 27.94

19.05

0.14 2.27

2.49 1.39

61.48 14.52

71.94 21.49

18.89

70.54 128.62

77.78 29.58

22.09

9.07 114.10

5.84 8.09

61.07 10.50

66.05 17.79

6.50

60.27 12.25

68.00 18.89

6.57

-0.80 1.75

1.95 1.10

54.84 6.02

62.44 13.08

7.62

60.74 119.25

68.16 19.01

7.90

5.90 113.24

5.71 5.93

104.70 46.57

112.84 54.75

45.73

107.18 41.75

114.08 51.21

46.50

2.48 -4.82

1.24 -3.54

108.57 48.95

118.14 57.92

44.57

117.11 158.38

129.50 63.28

52.97

8.54 109.44

11.36 5.37

63.51 17.77

73.56 30.21

15.08

65.31 23.28

81.14 36.07

17.79

1.80 5.51

7.58 5.86

50.58 6.47

63.20 19.68

16.56

69.40 26.11

83.19 40.16

18.71

18.82 19.64

20.00 20.48

63.80 18.05

73.29 30.39

15.35

65.46 21.96

77.22 33.72

15.41

1.66 3.91

3.93 3.33

56.57 13.41

68.55 25.08

18.27

68.54 132.57

80.07 36.19

18.98

11.98 119.16

11.52 11.11


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Based on ∆G values in Table 1, all HCNPs-X complexes are thermodynamically stable in both of the gas phase and DMSO. Moreover, HCNP1F‒ and HCNP2-F‒ complexes are the most stable structures in which a specific selectivity for anion is predictable. Charge transfer analysis In order to investigate the electrostatic and donor-acceptor interactions between HCNPs and different ions, NBO analysis was performed in the gas phase and DMSO. By employing this method, stabilization energy values, E(2), have been calculated. There is a linear correlation between E(2) values and the stability of HCNP-X complexes. This means that an increase in the stabilization energy, elevates the stability of the complexes. Table S4, shows all donor-acceptor interactions between lone pair electrons, LPO, LPF‒, LPBr‒ and LPCl‒ as donors with the antibonding orbital of N―H bonds (σ*N―H) as an acceptor. According to Table S4, DMSO affects the orbital interactions. For example, the interaction of LPO(OAC‒)→ σ*N13―H14(HCNP1) is absent in DMSO, while this interaction has a value of 20.79 kcal.mol-1 in the gas phase. Comparison between Tables S1 and S4, indicates that due to donor-acceptor interactions between Lp electrons of ions and σ*N―H, N―H bond length increases. For example, LpF‒→ σ*N7―H8 interaction of HCNP1 in DMSO has the maximum 14 ACS Paragon Plus Environment


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E(2) value (Table S4). According to Table S1, N7―H8 bond in HCNP1 in the presence of F‒ has the maximum bond length, which is similar to the behavior of the N5―H6 bond in HCNP2, due to LpF‒→ σ*N5―H6 interaction. According to calculated ∑E(2) values in Table 2, F‒ has the most interaction with HCNP1 and HCNP2 in the gas phase and DMSO. In the other words, F‒, due to strong electrostatic interactions, makes the most stable complexes with HCNP1 and HCNP2 in comparison to other ions, which is according to structural and energy analyses. Based on the, energy and NBO analyses, dispersion and electrostatic interactions are the driving forces for HCNPs-X complex formation. Table 2. Calculated ∑E(2) values (kcal.mol-1) of HCNP1 and HCNP2 complexes in the gas phase and DMSO at B3LYP-D3/6-311++G(d,p) level. LpF― → σ*N―H

LpBr―→ σ*N―H

Gas DMSO

LpO of OAC― → σ*N―H 150.10 109.93

152.03

141.81

143.25 74.85

Gas DMSO

129.72 84.69

121.36 86.37

27.80 30.42

HCNP1 LpO of HSO4― → σ*N―H 90.73 75.48

LpCl― → σ*N―H

LpO of NO3― → σ*N―H

14.41 22.47

60.22 48.30

35.34 16.60

80.00 69.14

HCNP2 76.74 77.78

Quantum chemistry reactivity indices and density of states (DOS) analysis To study the reactivity of HCNP1 and HCNP2 in selective complex formation with ions, HOMO-LUMO analysis has been performed and some quantum reactivity indices 50,51 such as electronic chemical hardness (η), electronic chemical potential (μ) and global electrophilicity index (ω) were calculated. 15 ACS Paragon Plus Environment

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According to Table 3, DMSO reduces the HOMO and LUMO energies (EHOMO and ELUMO, respectively) in comparison to the gas phase. Moreover, η values, which shows the energy gap of the structures, indicate that the reactivity of HCNP2 is more than HCNP1 in both of the gas phase and DSMO. Therefore, HCNP2 makes more stable complexes with different ions in comparison to HCNP1, which is according to Table 1. The energy gap of the HCNP1 in DMSO increases in the presence of OAC‒ which is in contrast to other ions. Similar behavior has been observed for HCNP2 in the presence of HSO4-. Calculated μ values, indicate that HCNP-X complexes have lower electronic chemical potential in comparison to the free hybrid cyclic nanopeptides. Electrophilicity value, stabilization in energy when a molecule acquires an additional electronic charge from the environment, reduces due to the complex formation similar to the μ and η indices. In order to confirm sensing ability of the HCNPs for different ions, density of states (DOS) analysis was performed. According to Figure 3, a significant change in the frontier orbitals of the HCNPs was seen in the presence of different ions, especially in the gas phase. Moreover, the comparison between the DOS spectra of the isolated HCNPs and their complexes shows a Fermi level shifting to higher values. These behaviors confirm a change in the corresponding conductivities which confirms the sensing ability of these HCNPs. 16 ACS Paragon Plus Environment


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Figure 3. DOS spectra of the HCNPs and their complexes in the gas phase and DMSO at the B3LYP-D3/6-31G(d) level.


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Table 3. Calculated quantum chemistry reactivity indices and HOMO-LUMO energies (a.u) of the free HCNPs and their complexes in the gas phase and DMSO at the B3LYP-D3/6-31G(d) level. EHOMO ELUMO η μ ω EHOMO ELUMO η μ ω HCNP1 HCNP2 -0.1041 0.0406 0.1447 -0.0317 0.0139 -0.1054 0.0271 0.1324 -0.0392 0.0001 OAC― Gas DMSO -0.2059 -0.0275 0.1783 -0.1167 0.1527 -0.2049 -0.0314 0.1735 -0.1182 0.0012 Gas -0.0997 0.0398 0.1395 -0.0300 0.0129 -0.1107 0.0304 0.1411 -0.0402 0.0001 Br― DMSO -0.2054 -0.0297 0.1756 -0.1175 0.1573 -0.2100 -0.0308 0.1792 -0.1204 0.0013

Cl― F― HSO4― NO3― HCNP

Gas DMSO Gas DMSO Gas DMSO Gas DMSO Gas DMSO

-0.0987 -0.2060 -0.1055 -0.2022 -0.1031 -0.2059 -0.1025 -0.2057 -0.1905 -0.2108

0.0351 -0.0305 0.0345 -0.0327 0.0405 -0.0289 0.0397 -0.0299 -0.0373 -0.0331

0.1338 0.1755 0.1400 0.1695 0.1436 0.1770 0.1422 0.1759 0.1531 0.1777

-0.0318 -0.1183 -0.0355 -0.1175 -0.0313 -0.1174 -0.0314 -0.1178 -0.1139 -0.1219

0.0151 0.1594 0.0180 0.1628 0.0136 0.1558 0.0139 0.1578 0.1694 0.1674

-0.1064 -0.2095 -0.1011 -0.2030 -0.1183 -0.2116 -0.1097 -0.2080 -0.1952 -0.2153

0.0254 -0.0316 0.0362 -0.0353 0.0383 -0.0288 0.0304 -0.0306 -0.0456 -0.0338

0.1318 0.1779 0.1374 0.1677 0.1565 0.1829 0.1401 0.1774 0.1497 0.1815

-0.0405 -0.1205 -0.0325 -0.1192 -0.0400 -0.1202 -0.0397 -0.1193 -0.1204 -0.1245

ELF, LOL and topological analysis For investigation of the X….HCNPs interactions, QTAIM analysis was applied at the bond critical points (BCP) of the X….H bonds. When the electron density (ρ) increases at the BCP, the interaction increases, too. According to Table 4, calculated ρ values of F‒….H bonds are bigger than other hydrogen and halogen bonds, which indicates that F‒ has stronger interaction with hybrid cyclic nanopeptides in comparison to other ions. Based on the negative values of the Laplacian (-

ρ), an electrostatic nature

of the ions and HCNPs interactions is confirmed. The ratio of the kinetic energy density (G) to the potential energy density (V), can be used as a criterion for determining the covalent or non-covalent interactions. According to Table 4, –G/V 18 ACS Paragon Plus Environment

0.0001 0.0013 0.0001 0.0012 0.0001 0.0013 0.0001 0.0013 0.0011 0.0014


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values of O2(OAC)….H12 ,Cl….H8 and Cl….H16 bonds of HCNP1 complexes and Br….H2 bond of HCNP2 complex are greater than 1.0, which show a non-covalent nature. Moreover, all F‒….H bonds have smaller –G/V values than other X….H bonds, which indicate a stronger covalent interaction. In the cases of other X ….H bonds, a partial covalent nature, has been confirmed because of –G/V values.


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Table 4. Calculated topological parameters of the X….H bonds of the HCNP-X complexes in the gas phase and DMSO at the B3LYP-D3/6-31G(d) level. BCP LOL ELF BCP LOL ELF BCP (ρ) -G/V (ρ) -G/V (ρ) -G/V HCNP1 Gas DMSO Gas DMSO Gas DMSO Gas DMSO Gas DMSO Gas DMSO Gas DMSO Gas DMSO Gas DMSO Gas DMSO Gas DMSO Gas DMSO Gas DMSO Gas DMSO Gas DMSO Gas DMSO

a

O1…H2

a

O1…H4

a

O2…H12

a

O2…H10 F‒…H6 F‒…H8 F‒…H10 F‒…H14

a

O1…H6

a

O1…H2

a

O2…H4

a

O2…H10 F‒…H8 F‒…H6 F‒…H18 F‒…H16

0.0341 0.0360 0.0204 0.0212 0.0162 0.0053 0.0258 0.0252 0.0374 0.0376 0.0533 0.0554 0.0359 0.0369 0.0368 0.0331

0.1079 0.0731 0.0656 0.0411 0.0522 0.0180 0.0751 0.0472 0.0673 0.0687 0.0944 0.0957 0.0626 0.0624 0.0641 0.0587

0.9648 0.8406 0.9843 0.8347 0.9990 1.1614 0.9400 0.8269 0.7697 0.7712 0.7467 0.7387 0.7650 0.7605 0.7647 0.7723

0.2686 0.1995 0.0644 0.1162 0.0491 0.0136 0.0956 0.1475 0.3335 0.3322 0.3778 0.3846 0.3323 0.3402 0.3356 0.3207

0.2686 0.3331 0.2080 0.2662 0.1852 0.1053 0.2454 0.2939 0.2001 0.1982 0.2693 0.2807 0.1984 0.2099 0.2032 0.1821

0.0294 0.0302 0.0168 0.0175 0.0302 0.0315 0.0232 0.0180 0.0211 0.0205 0.0333 0.0330 0.0496 0.0460 0.0269 0.0287

0.0552 0.0560 0.0341 0.0347 0.0583 0.0592 0.0476 0.0381 0.0401 0.0395 0.0560 0.0550 0.0829 0.0769 0.0516 0.0537

0.8287 0.8266 0.8450 0.8366 0.8361 0.8318 0.8424 0.8478 0.8175 0.8228 0.7687 0.7673 0.7466 0.7505 0.7968 0.7896

0.3164 0.3222 0.2316 0.2393 0.3167 0.3272 0.2695 0.2351 0.2633 0.2596 0.3309 0.3305 0.3802 0.3709 0.2860 0.2967

0.1763 0.1842 0.0831 0.0899 0.1763 0.1911 0.1197 0.0862 0.1131 0.1094 0.1964 0.1958 0.2734 0.2578 0.1381 0.1509

Br‒…H6 Br‒…H8

Br‒…H16 Br‒…H18 O3…H6

b

O3…H8

b

O3…H18

b

O4…H10

b

Br‒…H2 Br‒…H4 Br‒…H16 Br‒…H18 O4…H6

b

O4…H8

b

O3…H4

b

O3…H2

b

0.0140 0.0144 0.0133 0.0136 0.0121 0.0101 0.0203 0.0201 …… 0.0216 0.0147 0.0167 0.0206 0.0189 0.0146 0.0153

0.0258 0.0270 0.2599 0.0266 0.0243 0.0217 0.0340 0.0344 …… 0.0480 0.0377 0.0411 0.0463 0.0442 0.0389 0.0406

0.9826 0.9750 0.9560 0.9899 1.0261 1.0712 0.9107 0.9039 …… 0.8508 0.8903 0.8747 0.8521 0.8604 0.8985 0.9007

0.2627 0.2623 0.2480 0.2485 0.2358 0.2116 0.3125 0.3080 …… 0.2484 0.1915 0.2066 0.2408 0.2256 0.1861 0.1919

0.1123 0.1120 0.0978 0.0983 0.0866 0.0669 0.1709 0.1651 …… 0.983 0.0530 0.6342 0.0913 0.0871 0.0496 0.0533

1.0685 1.0214 0.9798 1.0041 0.9990 1.0084 1.0217 1.0232 0.8709 …… 0.9303 …… 0.9638 0.9556 0.8719 0.9835

0.2274 0.2416 0.2597 0.2433 0.2511 0.2476 0.2405 0.2355 0.2399 …… 0.1848 …… 0.1738 0.1775 0.2389 0.2244

0.0794 0.0918 0.1092 0.0935 0.1007 0.0974 0.0908 0.0864 0.0905 …… 0.0488 …… 0.0423 0.0444 0.0896 0.0772

Cl‒…H6 Cl‒…H8

Cl‒…H16 Cl‒…H18 O3…H6

c

O3…H8

c

O3…H18

c

O2…H10

c

HCNP2 0.0099 0.0116 0.0137 0.0124 0.0122 0.0122 0.0114 0.0115 0.0208 …… 0.0138 …… 0.0130 0.0135 0.0206 0.0241

0.0189 0.0220 0.0251 0.0239 0.0222 0.0225 0.0215 0.0223 0.0489 …… 0.0370 …… 0.0375 0.0390 0.0482 0.0787

a, b, and c are oxygen atoms of OAC―, HSO4― and NO3― ions, respectively.


Cl‒…H8 Cl‒…H6 Cl‒…H4 Cl‒…H2 O1…H18

c

O3…H16

c

O1…H2

c

O2…H4

c

LOL

ELF

0.0208 0.0206 0.0121 0.0116 0.0122 0.0087 0.0200 0.0183 0.0212 0.0226 0.0145 0.0165 0.0243 …… 0.0055 0.0089

0.0410 0.0415 0.0285 0.0277 0.0281 0.0220 0.0403 0.0385 0.0434 0.0459 0.0352 0.0390 0.0489 …… 0.0191 0.0263

0.9104 0.9125 1.0457 1.0000 1.0435 1.1457 0.9216 0.9315 0.8448 0.8414 0.8926 0.8763 0.8425 …… 1.1240 0.9756

0.2844 0.2791 0.2121 0.2049 0.2160 0.1782 0.2770 0.2607 0.2596 0.2678 0.1989 0.2124 0.2765 …… 0.1023 0.1410

0.1362 0.1303 0.0674 0.0621 0.0703 0.0447 0.1278 0.1104 0.1093 0.1178 0.0580 0.0677 0.1273 …… 0.0128 0.0262

0.0144 0.0110 0.0130 0.0139 0.0119 0.0093 0.0174 0.0161 0.0184 0.0180 0.0219 0.0218 0.0190 0.0197 0.0172 0.0170

0.0309 0.0261 0.0283 0.0304 0.0265 0.0223 0.0345 0.0338 0.0375 0.0367 0.0445 0.0445 0.0390 0.0401 0.0362 0.0359

0.9968 1.0745 1.0219 1.0032 1.0544 1.1324 0.9431 0.9626 0.8520 0.8532 0.8459 0.8463 0.8487 0.8461 0.8607 0.8619

0.2390 0.2046 0.2302 0.2322 0.2193 0.1907 0.2672 0.2512 0.2449 0.2416 0.2660 0.2642 0.2472 0.2510 0.2339 0.2313

0.0896 0.0619 0.0818 0.0836 0.0730 0.0524 0.1172 0.1009 0.0951 0.0920 0.1159 0.1141 0.0971 0.1008 0.0851 0.0829


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ELF and LOL analyses were performed and the results were reported in Table 4 and depicted in Figure 4. Large and small values of LOL and ELF show covalent and electrostatic interactions, respectively. According to Table 4 and Figure 4, low values of the ELF and LOL for the X….H(HCNPs) bonds indicate an electrostatic interaction.


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Figure 4. ELF and LOL plots of HCNP1-X (A) and HCNP2-X (B) complexes in the gas phase at the B3LYP-D3/6-31G(d) level.

Dynamical behaviors of hybrid cyclic nanopeptides in DMSO 25 ns molecular dynamic simulations were applied in DMSO, to investigate the dynamical behaviors of HCNP1 and HCNP2. Figure 5 shows the final obtained structures of HCNP1 and HCNP2 in DMSO in which only one ion enters in the cavity of the studied receptors, according to experimental data

47

. Based on this

figure, it reveals that HCNPs are more compact in the presence of F‒ in comparison to other ions. According to Figure S1-A which shows the calculated root mean square deviation (RMSD) values of HCNP1 with different ions, HCNP1 has the maximum RMSD in the presence of NO3‒. According to Table 5, the calculated maximum RMSD values of HCNP1 in the presence of OAC‒, Br‒, Cl‒, F‒, HSO4‒ and NO3‒ indicate that HCNP1 with F‒ form the most stable complex, based on their positions. Considering the radius of gyration (Rg) plots of HCNP1, Figure S1-B, it is confirmed that HCNP1….F‒ is the most compact complex. Moreover, average distance analysis between HCNP1 and different ions (Figure S1-C), during 25 ns MD simulations, confirms a strong interactions for F‒ in a theoretical trend of:



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F‒> OAC‒> Br‒> HSO4‒> NO3‒> Cl‒. Table 5. Obtained RMSD, average distance, electrostatic interaction energy and RDF values from 25 ns MD simulation on the HCNPs-X complexes in DMSO. Ions Maximum of Average Average ELE RDF (Å) Color RMSD (Å) distance (Å) (kcal.mol-1) HCNP1 5.63 3.77 -4005.28 2.15 Black OAC― Br― 6.56 5.64 -2197.35 2.05 Red ― Cl 9.56 8.86 -3699.73 2.05 Green ― F 3.01 3.54 -4899.01 1.95 Blue 6.04 5.93 -4598.12 1.85 Yellow HSO4― 12.77 6.01 -2440.91 2.15 Violet NO3― HCNP2 4.30 2.24 -4126.10 2.15 Black OAC― ― Br 2.83 3.83 -2529.19 2.05 Red ― 3.91 5.41 -3324.27 2.05 Green Cl F― 2.22 1.33 -6204.00 1.95 Blue 6.01 5.50 -4617.32 1.97 Yellow HSO4― 3.20 2.93 -3286.67 2.15 Violet NO3―

Figure S2-A shows the calculated RMSD plots of HCNP2-X complexes in which, HCNP2 with HSO4‒ and F‒ have the maximum and minimum RMSD, respectively. Reported data in Table 5 confirm that HCNP1 and HCNP2 have maximum RMSD in the presence of NO3‒ and HSO4‒, respectively, showing a different dynamical behavior for HCNPs in solution. Also, RMSD values show that HCNP2-X complexes in DMSO are more stable than HCNP1-X. The analysis of Rg plots of HCNP2-X structures (Figure S2-B) shows that HCNP2 similar to HCNP1 is the most compact complex structure in the presence of the F‒. Calculated average distance (Figure S2-C and Table 5) between HCNP2 and OAC‒, Br‒, Cl‒, F‒, HSO4‒ and NO3‒ are 2.24, 3.83 5.51, 1.33, 5.50 and 2.93 Å, 23 ACS Paragon Plus Environment

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respectively. Figure 6 shows the electrostatic interaction energy (ELE) between the H atoms (N―H groups) of HCNP1 and HCNP2 with different ions.

Figure 5. Obtained structures of HCNP1 (A) and HCPN2 (B) in presence of different ions in DMSO after 25 ns MD simulations. 24 ACS Paragon Plus Environment


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According to Figure 6, F‒ has the maximum electrostatic interaction with the HCNPs. Calculated average ELE in Table 5, confirms that HCNP2 has more interaction with ions than HCNP1, especially in the case of F‒. According to ELE values, the stability of HCNP2-X complexes is as follows: F‒> HSO4‒> OAC‒> Cl‒> NO3‒>Br‒. This trend is according to HCNP1 complexes.

Figure 6. Plots of the calculated electrostatic interaction energy between H atoms (N―H) groups and different ions for HCNP1 (A) and HCNP2 (B) in DMSO.

Figure 7, shows the radial distribution function (RDF) of the X….H (X….H―N) pairs of the HCNPs in DMSO. According to Figure 7-A, the first sharp peak of O….H pair (O atom of HSO4‒ ion) is at 1.85 Å, which confirms the H-bond formation between this ion and HCNP1. According to Figure 7-B, the probability of finding an X….H pair for HCNP2 is according to: F‒> HSO4‒> Br‒> Cl‒> OAC‒> NO3‒, which indicates that F‒ makes the most stable complex with HCNP2. 25 ACS Paragon Plus Environment

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Finally, MD simulations in DMSO reveal that F‒ in comparison to the other ions forms the most stable complex with HCNPs. Also, HCNP2 is a better receptor for selective complex formation with different ions. Obtained MD results are in a good agreement with DFT data.

Figure 7. RDF plots of X….H pairs of the HCNP1 (A) and HCNP2 (B) complexes in DMSO.

Conclusion Quantum chemistry calculations with M05-2X, M05-2X-D3, B3LYP and B3LYP-D3 functionals in the gas phase and DMSO were performed, to investigate the ability of HCNP1 and HCNP2 for selective complex formation with different ions. Obtained results confirm that HCNP1 and HCNP2 form selective complexes with F‒ and due to greater reactivity, HCNP2 is the better receptor. QM calculations reveal that dispersion and electrostatic interactions between HCNPs and ions have a key role in the complex formation. Due to the complex formation, 26 ACS Paragon Plus Environment


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Fermi level of the HCNPs shifted to higher values which indicates an acceptable sensing ability of the HCNPs for the studied ions. MD simulations in DMSO indicate that HCNPs are able to form 1:1 complexes with the studied ions. Calculated electrostatic interaction energies confirm that F‒has considerable interaction with HCNPs in comparison to other ions. Finally, there is a good agreement between the QM and MD results.

Supporting information Calculated structural parameters of the HCNP complexes in the gas phase and DMSO (Table S1), calculated halogen and hydrogen bond lengths (Table S2), calculated IR vibrational frequencies of the N―H bonds (Table S3), calculated E(2) energies of the complexes in the gas phase and DMSO (Table S4), RMSD, Rg and distance plots during 25 ns MD simulations in DMSO (Figures S1 and S2) and coordinates of the optimized complexes in the gas phase at the M05-2X/6-31G(d) level of theory.

Acknowledgement Research Council of Ferdowsi University of Mashhad is acknowledged for financial supports (Grant No. 2/38984). We hereby acknowledge that part of this computation was performed on the HPC center of Ferdowsi University of Mashhad. 27 ACS Paragon Plus Environment

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Table of Contents (TOC)

Sensing Activity of the Hybrid Cyclic Nanopeptides Based on Thiourea Cryptands


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Sensing Ability of Hybrid Cyclic Nanopeptides Based on Thiourea

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