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. 2023 Aug 17;28(16):6105. doi: 10.3390/molecules28166105

Theoretical Insights into a Near-Infrared Fluorescent Probe NI-VIS Based on the Organic Molecule for Monitoring Intracellular Viscosity

Yongjin Peng 1,*, He Huang 1, Yuling Liu 1, Xiaoyan Zhao 1,*
Editor: Barbara Panunzi1
PMCID: PMC10458998  PMID: 37630357

Abstract

So many biological functional disorders and diseases, such as atherosclerosis, hypertension, diabetes, Alzheimer’s disease, as well as cell malignancy are closely related with the intracellular viscosity. A safe and effective intracellular viscosity detecting method is desired by the biomedical community. Recently, a novel near-infrared fluorescent probe NI-VIS with a twisting intramolecular charge transfer mechanism was developed. The capability of this probe to visualize the viscosity variation in cirrhotic liver tissues and map the micro viscosity in vivo were testified using an experiment. In this work, the twisting intramolecular charge transfer mechanism and fluorescent properties of the probe NI-VIS were studied in detail under quantum mechanical method. The low energy barrier among the different conformations of the probe indicated the occurrence of twisting intramolecular charge transfer due to the rotation of the aryl group in the probe molecule while within the low viscosity environment. The electronic structure analysis on different probe conformations revealed the electron transfer process of the probe under optical excitation. All these theoretical results could provide insights into understand in greater depth the principles and build highly effective fluorescent probe to monitor the viscosity in biological samples.

Keywords: fluorescent probe, intracellular viscosity, density functional theory, electronic structure

1. Introduction

Viscosity plays an important role in all biological systems, from the microscopic level (such as cells) to the macroscopic level [1,2,3]. For viscous liquids under macroscopic conditions, it is easy to determine their viscosity with a viscometer. However, for liquids on a microscopic scale, such as in a single cell, the viscosity cannot be measured directly with a viscometer. More importantly, the micro viscosity is heterogeneous, with different components at different locations within the cell, such as cytoplasm, sub organelles, or membrane systems, having different viscosities [4,5,6,7,8,9]. Cell micro viscosity plays an important role in various biological processes, such as mass and energy transfer, signal transduction, interaction between biological macromolecules (proteins), active enzymes and cell metabolic rate, etc. [10,11,12,13,14,15,16]. Therefore, the design and synthesis of effective fluorescent probes for the determination of cell viscosity is of great significance for the study of cell physiological and pathological processes. So far, many fluorescence probes for the detection of viscosity have been reported in the literature [11,12,14,17,18,19,20,21,22,23,24,25,26,27,28].

A ratio-type fluorescent probe of viscosity was designed by Haidekker et al. [29]. They constructed a fluorescent resonance energy transfer (FRET) probe using two fluorescence groups, 2-cyano-3-(4-dimethylaminophenyl) acrylic acid methyl ester (CMAM) and 7-methoxycoumarin-3-carboxylic acid (MCCA). The fluorescence of MCCA part did not respond to viscosity changes, which could be used as the internal standard, and it was also the donor part of the FRET system. The fluorescence of the CMAM part increased with the increase in viscosity, and it was also the receptor part of the FRET system. The fluorescence of this probe had a good response to the viscosity change in the range of 1–400 mPa.s. The fluorescence emission ratio of CMAM and MCCA parts could eliminate the influence of the refractive index and dye concentration on the determination of viscosity. A BODIPY dye with a ferrocene structure as a viscosity probe was reported by Li et al. [30]. The ferrocene group was connected with the benzene ring of the BODIPY through a C-C triple bond, which could rotate freely between them, resulting in the formation of a TICT state in the electron excited state of the probe. This state attenuated to the ground state in a non-radiative way, thus reducing the fluorescence emission of probe. With the increase in viscosity, the free rotation of the C-C bond was limited, thus increasing the fluorescence emission of the probe. In the mixed solvent system of THF and ethylene glycol, the fluorescence emission of the probe increased with the increase in viscosity. The photo-physical properties and “8-Heteroaryl Effect” in 4,4-difluoro-8-(C4H3X)-4-bora-3a,4 a-diaza-s-indacene (X = O, S, Se)(BODIPY) systems were studied by Kim et al., who indicated the potential for this kind of structure to be explored as an experimental molecular fluorescent sensor applicate in life sciences [31]. The research on structural control of the photodynamics of boron-dipyrrin complexes by Kee et al. demonstrated the dominant role of aryl rotation in governing the excited state dynamics and fluorescent properties of aryl-substituted boron-dipyrrin dyes which facilitated the further use of this kind of dyes in life sciences and medical applications [32].

Miyashita et al. synthesized a green fluorescent protein (GFP) analogue to detect cholesterol content in the cellular phospholipid bilayer [33]. The probe consisted of a 4-(diphenyl) imidazolinone partially heterozygous with cholesterol. In the viscous solvent triglyceride, the fluorescence emission intensity of the probe increased with the increase in solvent viscosity. This property of the probe was also observed in the vesicles of the phospholipid bilayer. In the phospholipid bilayer, the fluorescence intensity of the probe increased with the increase in cholesterol content. A two-photon viscosity probe based on naphthalimide dye was reported by Meng et al. [34]. The fluorescence emission of this probe at 535 nm and its lifetime gradually increased with the increase in viscosity. Moreover, this probe could quantitatively detect changes in lysosome viscosity during autophagy in living cells by two-photon fluorescence lifetime imaging.

A NIR fluorescent probe NI-VIS which was utilized to create images of the mitochondrial viscosity in live cells was developed by Zhang et al. [35]. The probe NI-VIS used quinoline as an acceptor group and employed a TICT (twisted intramolecular charge transfer) mechanism to detect viscosity. A good mitochondrion targeting ability and near-infrared emission were featured in NI-VIS. The fluorescence of probe NI-VIS exhibited nearly a hundred-fold enhancement as the viscosity of a DPBS-glycerol system increased from 1.0 to 999.0 cP. Moreover, the probe NI-VIS was able to be used to map the micro-viscosity in vivo. All these results indicated that the probe NI-VIS can serve as a powerful tool to monitor the viscosity in biological samples and shows more potential in biomedical applications. The mechanism of fluorescence in probe NI-VIS responding to viscosity was studied through quantum chemistry calculation in this work. The stable structures of probe NI-VIS in ground and excited states were searched by optimization within the free energy surface. The discovered fluorescent mechanism of NI-VIS probe could be beneficial for providing insight in the design and synthetization of highly efficient fluorescent probes for application in the biomedical field.

2. Conformation Search

The processes of the conformation search for probe NI-VIS were as follows:

  • (1)

    Using Confab [36] to obtain initial conformations of probe NI-VIS;

  • (2)

    The batch structural optimization was conducted using Crest to invoke xtb program under the GFN2-xTB method [37];

  • (3)

    Invoke isostat in Molclus [38] program to screen out the several stable probe conformations with the local lowest free energy;

  • (4)

    The corresponding ground and excited state of different probe conformation’s structure optimization and vibrational frequency analysis on the stable probe conformations’ structure obtained from step (3) were conducted by using the ORCA program [39] under CAM-B3LYP/def2-TZVPD, a functional which was testified to be suitable for the excited state optimization with charge transfer character, with D3 dispersion correction and GCP correction to remove artificial overbinding effects from BSSE [40,41,42,43,44,45]. The functional and basis set combination wB2GP-PLYP/def2-TZVPD was used in a single point energy calculation to obtain the free energy with high precision [46,47,48,49,50,51,52,53,54]. Most of the figures in this work were rendered by means of VMD 1.9.3 software [55] and the analyses were finished by using the Multiwfn 3.8(dev) code [56].

3. Results and Discussion

The six most stable conformations of probe NI-VIS (named by NIA1, NIA2, NIB1, NIB2, NIC1 and NIC2, respectively) are shown in Figure 1 and summarized in Table 1. It can be seen that the variation of the dihedral angle α and β led to several different stable structures with local minimum free energy. While α and β were all 180°, the corresponding structure (NIC2) had the lowest free energy which meant that there was the least repulsion effect in NIC2. When α or β were 0°, the repulsion between the adjacent H atoms resulted in the increase in the free energy of the probe conformation. To reduce the repulsion effect, the changing of α from 0° to 24° would lead to the decrease in the free energy of the probe conformation (NIA1 compared to NIB1, NIA2 compared to NIB2). The 2-dimentional plots of electron densities in NIA2 and NIC2 were depicted in Figure 2. It could be clearly shown the torsion of the dihedral angle α in the NIA2 conformation.

Figure 1.

Figure 1

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Six most stable probe conformations of probe NI-VIS.

Table 1.

Parameters of six stable probe conformations.

α β ΔG (kcal/mol)
NIC2 Taken as Reference
NIA1 24° 0° 1.79
NIA2 24° 180° 0.88
NIB1 0° 0° 2.10
NIB2 0° 180° 1.05
NIC1 180° 0° 1.17
NIC2 180° 180° 0
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Figure 2.

Figure 2

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Two-dimensional plots of electron density of (a) NIA2 and (b) NIC2.

The most stable conformations of probe NI-VIS found here were different from the theoretical part discussed in reference [35]. In the reference the different conformations of probe NI-VIS were ascribed to the rotation of the C-C bond which connected the benzene ring and carbon chain but not the variation of the dihedral angle α and β, as shown in present study. The contradiction could be due to the incomplete basis set 6-31G*used in reference [35].

To obtain more information about the conformation difference in the probe NI-VIS, a structure optimization scan on dihedral angle α and β was conducted based on the former conformation search results. The 2D projection plot of different conformation’s free energy was shown in Figure 3. The dihedral angle scan steps were both chosen as 30° for α and β to save computational time. It could be clearly seen from Figure 3 that there were all six stable conformations with lower free energy which was consistent with the former conformation search results. The most stable conformation out of these six conformations was NIC2 with α and β both equal to 180°. The low free energy barrier, which was lower than 15 kcal/mol between different stable conformations, made the probe NI-VIS capable of taking different conformations within the low-viscosity solvent. This theoretical result was consistent with the experimental discussion in the reference [35].

Figure 3.

Figure 3

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Probe NI-VIS’ structure optimization scan on dihedral angle α and β, the unit of free energy E was Hatree.

The natural adaptive orbital (NAdO) distribution of corresponding rotating C-C bonds within α and β were analyzed with Multiwfn 3.8 (dev). From the 3D plot and 2D projection of the two C-C bonds’ NAdO distribution, as shown in Figure 4, Figure 5 and Figure 6, it could be found that the NAdO distribution of the α and β were almost the same.

Figure 4.

Figure 4

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NAdO distribution of α-related C-C bond in NIC1.

Figure 5.

Figure 5

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NAdO distribution of β-related C-C bond in NIC1.

Figure 6.

Figure 6

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NAdO distribution 2D projection of α and β-related C-C bond in NIC1.

To illustrate the interaction between atoms in the probe NI-VIS, the steric effect and vdW interaction within the conformation NIA2 analyzed via the interaction region indicator (IRI) method are depicted in Figure 7. It can be clearly seen that the variation of α from 0° to 24° enlarges the vdW interaction stabilizing the conformation NIA2 compared to the NIB2.

Figure 7.

Figure 7

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Interaction effect in NIA2.

4. Densities of States (DOS)

To understand the electron structures of probe NI-VIS, the DOS of probe NI-VIS was analyzed. It was found that all the conformations of probe NI-VIS had similar DOS structures. For clarity consideration, the DOS of NIC2 with lowest free energy was depicted in Figure 8 as an example. The whole probe molecule was divided into three parts with atom numbers 1–20 (I), 21–28 (II) and 29–47 (III) (the atom numbers can be referenced to Figures S1 and S2 in the supporting information). It can be clearly seen that the HOMO and LUMO contained the contribution of the three parts but at a different ratio. Part III contributed the most to HOMO, while part I contributed the most to LUMO. The electron transfer analysis in the optical excitation process within the probe NI-VIS also indicated the electron transfer from part III and part II to part I (quinoline), which was consistent with the DOS analysis results. From the atom–atom electron transfer analysis result (seen Figure 9), it can be seen that the electrons are mainly transfered from atom number 21, 25, 29, 39 within part III and part II to atom number 9, 12, 16 within part I.

Figure 8.

Figure 8

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DOS of NIC2, orange and green in color, in the molecule structure inset represented the distribution center of hole and electron, respectively, three parts I II and III indicated the atom numbers 1–20, 21–28 and 29–47 respectively.

Figure 9.

Figure 9

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Atom–atom electron transfer heat map of probe conformation NIC2.

5. Fluorescent Properties

To understand the fluorescent properties of probe NI-VIS, the optical excitation and emission process of the probe were analyzed using TD-DFT methods. The corresponding structure of ground state S0 and several lower excited states of different probe conformations were optimized, respectively. Other than the first excited state S1, no other low-lying dark states were found in each probe conformation’s excited states calculation. Meanwhile the S0/S1 conical intersection point search results (see Figure S4) indicated a large energy barrier between the CI point and the stable S1 and S0 structure which would lead to a radiative decay from S1 to S0 in the DE excitation process of each probe while they could not transfer between each other, due to being in a high viscosity environment. There were slight structure variations between the ground state S0 and the first excited state S1 within all six probe conformations. Within the conformations NIA1 and NIA2, the main variation of the structure between S0 and S1 was the dihedral α. It turned from about 24° in S0 to about 14° in S1. While within the other four conformations (α, β = 0° or 180°), the main variation of the structure between S0 and S1 was the angle θ, as shown in Figure 10, in which only NIC2 and NIA1 were shown as examples for clarity. The angle θ was almost turned from 130° in S0 to 136° in S1. The electron density difference between ground state S0 and first excited state S1 of the probe molecule NIC2 and NIA1 and the electron transfer from hole part to electron part while being under optical excitation are also shown in Figure 10, which indicated a local excitation process (π-π transition) occurs when the probe molecules are optically excited. The detailed analysis of optical excitation and emission process within all six stable probe conformations are summarized in Table 2 and Table 3. It could be seen that the calculated central wavelength of excitation and emission process were about 540 nm and 650 nm, which was consistent with the experimental value reported in reference [35]. While in a low-viscosity environment, the lower energy barrier between different stable probe conformations (lower than 15 kcal/mol, as shown in Figure 3) led to an easy transfer between the different stable probe conformations, which provided a efficient non-radiative way for the DE excitation of the probe molecule and caused very low intensity of the fluorescence in this situation. The increasing viscosity of the environment would effectively cut off the transfer way between different stable probe conformations which trapped the probe molecule in the few conformations with lower free energy and led to a significant enhancement of the fluorescence just as exhibited in the experimental research.

Figure 10.

Figure 10

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Theoretical calculations on the electron excitation and emission process of the probe molecule NIC2 and NIA1 (orange part represents a hole, green part represents an electron).

Table 2.

The main electron excitation processes in the probe molecule.

Probe Electronic
Transition a 		Excitation
Energy		 Oscillator
Strength		 Composition b CI c
NIA1 S0 → S1 548 nm 2.0151 H → L+1
H → L
H-1 → L		 0.1002
0.6941
0.1124
NIA2 S0 → S1 553 nm 1.8795 H-1 → L
H → L		 0.1005
0.6825
NIB1 S0 → S1 537 nm 0.9696 H → L
H-1 → L		 0.6941
0.1127
NIB2 S0 → S1 545 nm 1.4352 H → L
H-1 → L		 0.6501
0.1141
NIC1 S0 → S1 518 nm 1.8625 H → L
H-1 → L		 0.6786
0.1064
NIC2 S0 → S1 527 nm 1.9992 H → L
H-1 → L		 0.6875
0.1129
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a: Only the excited states with oscillator strength larger than 0.1 were considered. b: H stands for HOMO and L stands for LUMO. c: Coefficient of the wave function for each excitation was in absolute value.

Table 3.

The main emission processes in the probe molecule.

Probe Electronic
Transition a 		Emission
Energy		 Oscillator
Strength		 Composition b CI c
NIA1 S1 → S0 662 nm 2.1046 H → L 0.6835
NIA2 S1 → S0 658 nm 2.0135 H → L 0.6932
NIB1 S1 → S0 651 nm 2.2160 H → L 0.7067
NIB2 S1 → S0 640 nm 2.2504 H → L 0.6665
NIC1 S1 → S0 637 nm 2.2312 H → L 0.7153
NIC2 S1 → S0 645 nm 2.3014 H → L 0.7018
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a,b,c same indication as in Table 2.

To further understand the character of the electron excitation process of the probe NI-VIS, the directional UV-Vis spectrum of the different probe conformations was studied using TD-DFT methods. The theoretical results indicated the main absorbed electric field by the probe NI-VIS in the excitation process lied within the probe molecular plane while the electric field which vibrated perpendicular to the molecular plane (z-axis in Figure 11) was barely absorbed by the probe molecule. Only the directional UV-Vis spectrum of probe conformation NIC2 was depicted in Figure 11 for clarity purposes. The reorganization energy between ground state S0 and first excited state S1 of different probe NI-VIS conformation were calculated. It can be seen in Figure 12 (NIC2) that the main vibration contribution to the reorganization energy was the torsion of the C-H bond. The reorganization energy between ground state S0 and first excited state S1 of NIA2 could be referenced in Figure S3 of supporting information.

Figure 11.

Figure 11

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The directional UV-Vis spectrum of the probe conformation NIC2.

Figure 12.

Figure 12

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Reorganization energy of NIC2 (S0 to S1).

6. Conclusions

Different stable conformations of near-infrared fluorescent probe NI-VIS were found using the quantum chemical theoretical method. The calculated low energy barrier among different probe conformations indicated the structure variation of the probe NI-VIS in the low viscosity environment, which provided the efficient non-radiative way for the DE excitation of the probe molecule and caused the very low intensity of the fluorescence in this situation. The increasing viscosity of the environment would effectively cut off the transfer pathway between different stable probe conformations, which trapped the probe molecule in the few conformations with lower free energy and led to a significant fluorescence enhancement. The analysis of the related C-C bond combined with the interaction effect indicated the C-C bond rotation was the origin of the structure variation occurring in the probe molecule. The electron transfer analysis within the optical excitation and emission process indicated that the quinolone group in the probe molecule acted as an electron acceptor. The main electric field absorbed by the probe NI-VIS in the optical excitation process lay within the probe molecular plane while the electric field, which vibrated perpendicular to the molecular plane, was barely absorbed. All the above theoretical results could provide insights to deepen our understanding and design a highly efficient fluorescent probe monitoring viscosity which could be applied in the biological field.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28166105/s1, Figure S1: The stable structure of NIA2; Figure S2: The stable structure of NIC2; Figure S3: Reorganization energy of NIA2 (S0 to S1); Figure S4: S0/S1 conical intersection point search results of NIC2.

Click here for additional data file. (478KB, zip)

Author Contributions

Conceptualization, Y.P.; methodology, Y.P. and X.Z.; software, H.H.; formal analysis, Y.P. and Y.L.; investigation, Y.P. and H.H.; writing—original draft preparation, Y.P.; writing—review and editing, Y.P.; funding acquisition, Y.P. and X.Z. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Corresponding data could be obtained on request through author’s email.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Not applicable.

Funding Statement

This work was supported by the Natural Science Foundation of Liaoning Province (2022-MS-389, JYTQN201923, 20180550512).

Footnotes

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References

  • 1.Puchkov E.O. Intracellular Viscosity: Methods of Measurements and Role in Metabolism. Biol. Membr. 2014;31:3–13. doi: 10.1134/S1990747813050140. [DOI] [Google Scholar]
  • 2.Kuimova M.K., Botchway S.W., Parker A.W., Balaz M., Collins H.A., Anderson H.L., Suhling K., Ogilby P.R. Imaging intracellular viscosity of a single cell during photoinduced cell death. Nat. Chem. 2009;1:69–73. doi: 10.1038/nchem.120. [DOI] [PubMed] [Google Scholar]
  • 3.Garcia-Seisdedos H., Heidenreich M., Levy E.D. Not Going with the Flow: How Cells Adapt Internal Physics. Cell. 2020;183:1462–1463. doi: 10.1016/j.cell.2020.11.021. [DOI] [PubMed] [Google Scholar]
  • 4.Begum H.M., Shen K. Intracellular and microenvironmental regulation of mitochondrial membrane potential in cancer cells. Wires Mech. Dis. 2023;15:e1595. doi: 10.1002/wsbm.1595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Noh K., Uthaman S., Lee C.-S., Kim Y., Pillarisetti S., Hwang H.S., Park I.-K., Huh K.M. Tumor intracellular microenvironment-responsive nanoparticles for magnetically targeted chemotherapy. J. Ind. Eng. Chem. 2022;111:121–128. doi: 10.1016/j.jiec.2022.03.042. [DOI] [Google Scholar]
  • 6.Lin K.-H., Chiang J.-C., Ho Y.-H., Yao C.-L., Lee H. Lysophosphatidic Acid and Hematopoiesis: From Microenvironmental Effects to Intracellular Signaling. Int. J. Mol. Sci. 2020;21:2015. doi: 10.3390/ijms21062015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Ji K., Mayernik L., Moin K., Sloane B.F. Acidosis and proteolysis in the tumor microenvironment. Cancer Metastasis Rev. 2019;38:103–112. doi: 10.1007/s10555-019-09796-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Sulerud T., Pelletier J., Tomschik M., Noren B.E., Kloxin A.M., Oakey J.S., Gatlin J.C. Elucidating the mechanics of aster positioning using labile hydrogel microenvironments. Mol. Biol. Cell. 2017;28:4832–4841. [Google Scholar]
  • 9.Chen B., Dai W., He B., Zhang H., Wang X., Wang Y., Zhang Q. Current Multistage Drug Delivery Systems Based on the Tumor Microenvironment. Theranostics. 2017;7:538–558. doi: 10.7150/thno.16684. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Xie D., Ma W., Wang C., Zhang W., Ding Z. Mitochondria-targeted fluorescent probe for imaging viscosity in hepatic ischemia-reperfusion injury cell model. Chem. Commun. 2023;59:1030–1033. doi: 10.1039/D2CC06238K. [DOI] [PubMed] [Google Scholar]
  • 11.Samanta S.K., Maiti K., Halder S., Guria U.N., Mandal D., Jana K., Mahapatra A.K. A ‘double locked’ ratiometric fluorescent probe for detection of cysteine in a viscous system and its application in cancer cells. Org. Biomol. Chem. 2023;21:575–584. doi: 10.1039/D2OB01813F. [DOI] [PubMed] [Google Scholar]
  • 12.Wu Y., Yin C., Zhang W., Zhang Y., Huo F. Mitochondrial-Targeting Near-Infrared Fluorescent Probe for Visualizing Viscosity in Drug-Induced Cells and a Fatty Liver Mouse Model. Anal. Chem. 2022;94:5069–5074. doi: 10.1021/acs.analchem.1c05288. [DOI] [PubMed] [Google Scholar]
  • 13.Wang Y., Lei T., Zhang J., Gong L., Yang Y., Ma X., Wen Y., Du H., Qi D., Bian Y., et al. A porphyrin-triazatruxene dyad for ratiometric two-photon fluorescent sensing of intracellular viscosity. J. Mater. Chem. B. 2022;10:5487–5492. doi: 10.1039/D2TB00384H. [DOI] [PubMed] [Google Scholar]
  • 14.Wang M.-H., Cui W.-L., Yang Y.-H., Wang J.-Y. Viscosity-Sensitive Solvatochromic Fluorescent Probes for Lipid Droplets Staining. Biosensors. 2022;12:851. doi: 10.3390/bios12100851. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Pittman M., Ali A.M., Chen Y. How sticky? How tight? How hot? Imaging probes for fluid viscosity, membrane tension and temperature measurements at the cellular level. Int. J. Biochem. Cell Biol. 2022;153:106329. doi: 10.1016/j.biocel.2022.106329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Pan X., Wang C., Zhao C., Cheng T., Zheng A., Cao Y., Xu K. Assessment of cancer cell migration using a viscosity-sensitive fluorescent probe. Chem. Commun. 2022;58:4663–4666. doi: 10.1039/D1CC07235H. [DOI] [PubMed] [Google Scholar]
  • 17.Li F., Zhou B.-Z., Yao W., Sun S.-K., Miao J.-Y., Zhao B.-X., Lin Z.-M. Dual-response and lysosome-targeted fluorescent probe for viscosity and sulfur dioxide derivatives. Anal. Chim. Acta. 2023;1239:340721. doi: 10.1016/j.aca.2022.340721. [DOI] [PubMed] [Google Scholar]
  • 18.Jo S., Kim S., Lee Y., Kim G., Kim S., Lee S., Lee T.S. Synthesis of a dual-emissive pyrene-based fluorescent probe for imaging intracellular viscosity. J. Photochem. Photobiol. A-Chem. 2022;433:114147. doi: 10.1016/j.jphotochem.2022.114147. [DOI] [Google Scholar]
  • 19.Fu M., Wang K., Ma Q., Zhu J., Bian M., Zhu Q. A novel dual-functional fluorescent probe for imaging viscosity and cysteine in living system. Org. Biomol. Chem. 2022;20:672–677. doi: 10.1039/D1OB02116H. [DOI] [PubMed] [Google Scholar]
  • 20.Maleckaite K., Dodonova J., Toliautas S., Zilenaite R., Jurgutis D., Karabanovas V., Tumkevicius S., Vysniauskas A. Designing a Red-Emitting Viscosity-Sensitive BODIPY Fluorophore for Intracellular Viscosity Imaging. Chem.-A Eur. J. 2021;27:16768–16775. doi: 10.1002/chem.202102743. [DOI] [PubMed] [Google Scholar]
  • 21.Wang S., Zhou B., Wang N., Yu C., Yang N., Chen J., Wu Q., Zhang C., Li L., Huang W. Mitochondria-targeted fluorescent probe based on vibration-induced emission for real-time monitoring mitophagy-specific viscosity dynamic. Chin. Chem. Lett. 2020;31:2897–2902. doi: 10.1016/j.cclet.2020.03.037. [DOI] [Google Scholar]
  • 22.Ma C., Sun W., Xu L., Qian Y., Dai J., Zhong G., Hou Y., Liu J., Shen B. A minireview of viscosity-sensitive fluorescent probes: Design and biological applications. J. Mater. Chem. B. 2020;8:9642–9651. doi: 10.1039/D0TB01146K. [DOI] [PubMed] [Google Scholar]
  • 23.Fu M., Shen W., Chen Y., Yi W., Cai C., Zhu L., Zhu Q. A highly sensitive red-emitting probe for the detection of viscosity changes in living cells, zebrafish, and human blood samples. J. Mater. Chem. B. 2020;8:1310–1315. doi: 10.1039/C9TB02023C. [DOI] [PubMed] [Google Scholar]
  • 24.Chen L., Feng Y., Dang Y., Zhong C., Chen D. A deep-red emission fluorescent probe with long wavelength absorption for viscosity detection and live cell imaging. Anal. Bioanal. Chem. 2020;412:7819–7826. doi: 10.1007/s00216-020-02911-2. [DOI] [PubMed] [Google Scholar]
  • 25.Zhang G., Ni Y., Zhang D., Li H., Wang N., Yu C., Li L., Huang W. Rational design of NIR fluorescence probes for sensitive detection of viscosity in living cells. Spectrochim. Acta Part A-Mol. Biomol. Spectrosc. 2019;214:339–347. doi: 10.1016/j.saa.2019.02.068. [DOI] [PubMed] [Google Scholar]
  • 26.Ning P., Dong P., Geng Q., Bai L., Ding Y., Tian X., Shao R., Li L., Meng X. A two-photon fluorescent probe for viscosity imaging in vivo. J. Mater. Chem. B. 2017;5:2743–2749. doi: 10.1039/C7TB00136C. [DOI] [PubMed] [Google Scholar]
  • 27.Lee S.-C., Heo J., Ryu J.-W., Lee C.-L., Kim S., Tae J.-S., Rhee B.-O., Kim S.-W., Kwon O.P. Pyrrolic molecular rotors acting as viscosity sensors with high fluorescence contrast. Chem. Commun. 2016;52:13695–13698. doi: 10.1039/C6CC06521J. [DOI] [PubMed] [Google Scholar]
  • 28.Peng X., Yang Z., Wang J., Fan J., He Y., Song F., Wang B., Sun S., Qu J., Qi J., et al. Fluorescence Ratiometry and Fluorescence Lifetime Imaging: Using a Single Molecular Sensor for Dual Mode Imaging of Cellular Viscosity. J. Am. Chem. Soc. 2011;133:6626–6635. doi: 10.1021/ja1104014. [DOI] [PubMed] [Google Scholar]
  • 29.Haidekker M.A., Brady T.P., Lichlyter D., Theodorakis E.A. A ratiometric fluorescent viscosity sensor. J. Am. Chem. Soc. 2006;128:398–399. doi: 10.1021/ja056370a. [DOI] [PubMed] [Google Scholar]
  • 30.Yin X., Li Y., Zhu Y., Jing X., Li Y., Zhu D. A highly sensitive viscosity probe based on ferrocene-BODIPY dyads. Dalton Trans. 2010;39:9929–9935. doi: 10.1039/c0dt00309c. [DOI] [PubMed] [Google Scholar]
  • 31.Kim K., Jo C., Easwaramoorthi S., Sung J., Kim D.H., Churchill D.G. Crystallographic, Photophysical, NMR Spectroscopic and Reactivity Manifestations of the “8-Heteroaryl Effect” in 4,4-Difluoro-8-(C4H3X)-4-bora-3a,4a-diaza-s-indacene (X=O, S, Se) (BODIPY) Systems. Inorg. Chem. 2010;49:4881–4894. doi: 10.1021/ic902467h. [DOI] [PubMed] [Google Scholar]
  • 32.Kee H.L., Kirmaier C., Yu L., Thamyongkit P., Youngblood W.J., Calder M.E., Ramos L., Noll B.C., Bocian D.F., Scheidt W.R., et al. Structural Control of the Photodynamics of Boron? Dipyrrin Complexes. J. Phys. Chem. B. 2005;109:20433–20443. doi: 10.1021/jp0525078. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Ikejiri M., Mori K., Miyagi R., Konishi R., Chihara Y., Miyashita K. A hybrid molecule of a GFP chromophore analogue and cholestene as a viscosity-dependent and cholesterol-responsive fluorescent sensor. Org. Biomol. Chem. 2017;15:6948–6958. doi: 10.1039/C7OB01522D. [DOI] [PubMed] [Google Scholar]
  • 34.Hou L., Ning P., Feng Y., Ding Y., Bai L., Li L., Yu H., Meng X. Two-Photon Fluorescent Probe for Monitoring Autophagy via Fluorescence Lifetime Imaging. Anal. Chem. 2018;90:7122–7126. doi: 10.1021/acs.analchem.8b01631. [DOI] [PubMed] [Google Scholar]
  • 35.Zhang Y., Li Z., Hu W., Liu Z. A Mitochondrial-Targeting Near-Infrared Fluorescent Probe for Visualizing and Monitoring Viscosity in Live Cells and Tissuese. Anal. Chem. 2019;91:10302–10309. doi: 10.1021/acs.analchem.9b02678. [DOI] [PubMed] [Google Scholar]
  • 36.O’Boyle N.M., Vandermeersch T., Flynn C.J., Maguire A.R., Hutchison G.R. Confab—Systematic generation of diverse low-energy conformers. J. Cheminform. 2011;3:8–16. doi: 10.1186/1758-2946-3-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Bannwarth C., Ehlert S., Grimme S. GFN2-xTB-An Accurate and Broadly Parametrized Self-Consistent Tight-Binding Quantum Chemical Method with Multipole Electrostatics and Density-Dependent Dispersion Contributions. J. Chem. Theory Comput. 2019;15:1652–1671. doi: 10.1021/acs.jctc.8b01176. [DOI] [PubMed] [Google Scholar]
  • 38.Lu T. Molclus Program, Version 1.9.9.3. [(accessed on 11 February 2021)]. Available online: https://www.keinsci.com/research/molclus.html.
  • 39.Neese F. Software update: The ORCA program system, version 4.0. Wiley Interdiscip. Rev. Comput. Mol. Sci. 2018;8:e1327. doi: 10.1002/wcms.1327. [DOI] [Google Scholar]
  • 40.Grimme S., Ehrlich S., Goerigk L. Effect of the damping function in dispersion corrected density functional theory. J. Comput. Chem. 2011;32:1456–1465. doi: 10.1002/jcc.21759. [DOI] [PubMed] [Google Scholar]
  • 41.Weigend F., Ahlrichs R. Balanced basis sets of split valence, triple zeta valence and quadruple zeta valence quality for H to Rn: Design and assessment of accuracy. PCCP. 2005;7:3297–3305. doi: 10.1039/b508541a. [DOI] [PubMed] [Google Scholar]
  • 42.Ghosh S., Verma P., Cramer C.J., Gagliardi L., Truhlar D.G. Combining Wave Function Methods with Density Functional Theory for Excited States. Chem. Rev. 2018;118:7249–7292. doi: 10.1021/acs.chemrev.8b00193. [DOI] [PubMed] [Google Scholar]
  • 43.Shu Y., Parker K.A., Truhlar D.G. Dual-Functional Tamm-Dancoff Approximation: A Convenient Density Functional Method that Correctly Describes S-1/S-0 Conical Intersections. J. Phys. Chem. Lett. 2017;8:2107–2112. doi: 10.1021/acs.jpclett.7b00594. [DOI] [PubMed] [Google Scholar]
  • 44.Gagliardi L., Truhlar D.G., Li Manni G., Carlson R.K., Hoyer C.E., Bao J.L. Multiconfiguration Pair-Density Functional Theory: A New Way To Treat Strongly Correlated Systems. Acc. Chem. Res. 2017;50:66–73. doi: 10.1021/acs.accounts.6b00471. [DOI] [PubMed] [Google Scholar]
  • 45.Yu H.S., Li S.L., Truhlar D.G. Perspective: Kohn-Sham density functional theory descending a staircase. J. Chem. Phys. 2016;145:130901. doi: 10.1063/1.4963168. [DOI] [PubMed] [Google Scholar]
  • 46.Casanova-Paez M., Goerigk L. Assessing the Tamm-Dancoff approximation, singlet-singlet, and singlet-triplet excitations with the latest long-range corrected double-hybrid density functionals. J. Chem. Phys. 2020;153:064106. doi: 10.1063/5.0018354. [DOI] [PubMed] [Google Scholar]
  • 47.Goerigk L., Grimme S. Double-hybrid density functionals. Wiley Interdiscip. Rev.-Comput. Mol. Sci. 2014;4:576–600. doi: 10.1002/wcms.1193. [DOI] [Google Scholar]
  • 48.Casanova-Páez M., Dardis M.B., Goerigk L. ωB2PLYP and ωB2GPPLYP: The First Two Double-Hybrid Density Functionals with Long-Range Correction Optimized for Excitation Energies. J. Chem. Theory Comput. 2019;15:4735–4744. doi: 10.1021/acs.jctc.9b00013. [DOI] [PubMed] [Google Scholar]
  • 49.Liu Y.-l., Huang H., Peng Y.-j. Fluorescent probe for simultaneous detection of human serum albumin and sulfite: A theoretical analysis. J. Mol. Struct. 2022;1255:132441. doi: 10.1016/j.molstruc.2022.132441. [DOI] [Google Scholar]
  • 50.Jia A., Huang H., Zuo Z.-f., Peng Y.-j. Electronic structure and interaction in CH4@C-60: A first-principle investigation. J. Mol. Model. 2022;28:179. doi: 10.1007/s00894-022-05172-1. [DOI] [PubMed] [Google Scholar]
  • 51.Peng Y.-J., Huang H., Wang C.-J. DFT investigation on electronic structure, chemical bonds and optical properties of Cu-6(SR)(6) nanocluster. Chem. Phys. Lett. 2021;780:138898. doi: 10.1016/j.cplett.2021.138898. [DOI] [Google Scholar]
  • 52.Liu P., Liu Y.-L., Huang H., Bai G., Peng Y.-J. Theoretical investigation on FRET strategy of ratio metric fluorescent probe sensing hydrogen sulfide. Spectrochim. Acta Part A-Mol. Biomol. Spectrosc. 2023;289:122223. doi: 10.1016/j.saa.2022.122223. [DOI] [PubMed] [Google Scholar]
  • 53.Lin X.Y., Sun S.H., Liu Y.T., Shi Q.Q., Lv J.J., Peng Y.J. Thiophene and diaminobenzo-(1,2,5-thiadiazol)- based DAD-type near-infrared fluorescent probe for nitric oxide: A theoretical research. Front. Chem. 2023;10:990979. doi: 10.3389/fchem.2022.990979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Li D., Wang G., Peng Y., Chen Z., Gao X., Cheng L., Mei X. Development of ratiometric sensing and white light-harvesting materials based on all-copper nanoclusters. Nanoscale Adv. 2019;1:1086–1095. doi: 10.1039/C8NA00224J. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Humphrey W., Dalke A., Schulten K.K. VMD—Visual molecular dynamics. J. Mol. Graph. 1995;14:33–38. doi: 10.1016/0263-7855(96)00018-5. [DOI] [PubMed] [Google Scholar]
  • 56.Lu T., Chen F. Multiwfn: A multifunctional wavefunction analyzer. J. Comput. Chem. 2012;33:580–592. doi: 10.1002/jcc.22885. [DOI] [PubMed] [Google Scholar]

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