Glutathione-Coated Au29(SG)27: Structural Determination Based on

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C: Physical Processes in Nanomaterials and Nanostructures 29

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Glutathione-Coated Au (SG) : Structural Determination Based on Different Combination Styles Confirmed by Experiments Kaiyi Wang, Wenyong Su, Fuping Gao, Xueyun Gao, Wenchao Niu, Haodong Yao, Xiaofeng Wang, and Lina Zhao J. Phys. Chem. C, Just Accepted Manuscript • DOI: 10.1021/acs.jpcc.9b01184 • Publication Date (Web): 14 May 2019 Downloaded from http://pubs.acs.org on May 14, 2019

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The Journal of Physical Chemistry

Glutathione-Coated Au29(SG)27: Structural Determination Based on Different Combination Styles Confirmed by Experiments Kaiyi Wanga,b, Wenyong Sua, Fuping Gaob, Xueyun Gaoc, Wenchao Niub,c, Haodong Yaob, Xiaofeng Wangb, and Lina Zhao*b a.School

b.Key

of Physics, Beijing Institute of Technology, Beijing 100081, China.

Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China. .

c.Department

of Chemistry and Chemical Engineering, Beijing University of Technology, Beijing 100124, China.

ABSTRACT: Glutathione-coated small-sized gold nanocluster denoted as Au29(SG)27 has potential applications in bio therapeutics. Since it is difficult to obtain an accurate atomic structure experimentally, its structure is predicted by density functional theory. The atomic structure of Au29(SG)27 is speculated to contain a ring motif (for low Au/S ratio), the Au4 core and staple motifs (by “divide and protect” method). In the structural optimization, we proposed the four various combination styles, and took the second and third combinations respectively when N≤6 and N>6 (N is the number of Au atoms in the ring motif). All stable isomers are sorted by energy, and the

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structure with the lowest energy (isomer 1) consists of Au7(SCH3)7 ring motif and an Au4 core attached staple motifs as Au4Au8(SCH3)9Au10(SCH3)11. Then we calculated and analyzed the atomic and electronic structures of isomer 1. The electronic transition of HOMO-LUMO is mainly the transition from d orbital to p orbital, which is within gold core or between gold core and the ring motif. The UV-vis absorption spectrum calculated by TDDFT is in good agreement with the experimental measurement to confirm the atomic structure of Au29(SG)27 predicted by combination style strategy.

1. INTRODUCTION In recent years, the gold nanoparticles (AuNPs) have aroused great interests in the applications of the detection of biomolecules,1,2 the design of nano bioprobes,3,4 and nanomedicine.5—7 Due to the good biocompatibility and low toxicity. The AuNPs have been potentially utilized in the treatment of tumors.8 The study showed that the radiation doses of tumor tissue added to Au can be increased to 200% or higher relative to that of normal tissues without Au.9, 10 The AuNPs interact with radiation directly after receiving incident radiation (such as gamma rays, X-rays), become a new source of radiation and emit high energy to cause damage to surrounding tumor tissue.11,12 However, the core size of AuNPs and the protective ligands on the surface affect its distribution in the organism, which may be absorbed by the reticuloendothelial system (RES) resulting in low tumor absorption and inevitable accumulation in the liver13,14 leading to potential toxicity.15 It is necessary to select small size gold nanoclusters (AuNCs) with a core size of less than 2 nm. The AuNCs have the better biocompatibility than that of AuNPs by combining the two key factors of core size and coating ligands. Naturally occurring amino acids contribute to the synthesis of AuNCs with improved performance.16 Glutathione (γ-glutamate-cysteine-glycine, GSH) is a naturally occurring tri-peptide that is widely distributed in biological cells.17 Studying


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the excited state behavior of glutathione-protected gold nanoclusters can understand their photocatalytic activity in the visible region.18 Moreover, it has a variety of physiological functions that remove harmful organic oxides and free radicals. The GSH binds to the toxins, allowing it to be excreted in the urine or bile, helping the cells to be detoxifying.19 The AuNCs coating with GSH ligands have excellent biocompatibility, which can provide a good interface for biological systems, enhance their deposition in tumors, and reduce the biotoxicity to normal tissues.20 As a surface ligand, GSH can enhance the radiosensitization of ultra-small gold nanoparticles (The diameter is about 2 nm).21 It has been proven that the drug delivery system based on nanocluster was feasible by using GSH as a release agent.22 Ultra-small GSH coated AuNC (Au10-12(SG)10-12) molecules can increase tumor uptake and targeting specificity.23 Later, it was reported that Au29-43(SG)27-37 escaped RES absorption with high tumor accumulation by an improved enhanced permeability and retention (EPR) effect, which revoked no significant toxicity in vivo.24 The stable ligand GSH could compete with BSA (or cytochrome C) and form GSH-terminated AuNC, which increased the uptake of AuNCs by human breast cancer cells.25,26 In addition, intracellular GSH was used as a reducing and blocking agent to directly produce fluorescent AuNC in cells, showing confocal imaging of cancer cells.27 PeptideAu cluster compounds can efficiently induce tumor cell apoptosis by recognizing and binding specific domains of Glutathione peroxidase-1 (GPx-1) with high affinity.28 The glutathione-coated Au25(SG)18 also showed good photothermal activity and could be used for in vitro photothermia therapy of breast cancer cells.29 The Au29(SG)27 was synthesized recently in experiments, and it was discovered the potential applications inarthritis treatment.30 The significant biomedical functions stem from the spatial structure. However, the precise atomic structure of Au29(SG)27 is missing because its crystal is


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extremely difficult to be obtained in experiments. Fortunately, theoretical means can provide the atomic structure prediction for Au29(SG)27. In this study, we used density functional theory (DFT) to calculate the atomic structure of Au29(SG)27. In the atomic structure prediction of GSH coated AuNCs, the thiolated methyl is introduced to substitute SG to reduce the computational consumption reasonably. According to previous studies, it did not affect the optical absorption when the –SG ligand was replaced by -SCH3 ligand. The experimental UV-vis absorption spectra of Au25(SG)18-, Au25(SC6H13)18-31,32 and Au25(SC2H4Ph)18-33 were very similar, which indicated the atomic structure of AuNC coating by ligands cannot be affected significantly by the conversion of -SG to other ligands like -SR ligands. In order to further test the effect of SG on optical absorption, Jiang et al. replaced a -SCH3 of Au15(SCH3)13 with -SG to construct Au15(SCH3)12(SG)1 and calculated its optical absorption spectrum. The calculated optical absorption was very similar to that of Au15(SCH3)13, indicating that the optical absorption of Au15(SR)13 was not significantly changed by the ligand changing from -SCH3 to –SG. 34 Therefore, it is reasonable to replace -SG with -SGH3 in our system denoted as Au29(SCH3)27.The Au/S ratio is a key starting point to decompose the atomic structure of ligand coated AuNCs. The staple motif structure of -S-Au-Sis a basic unit in the composition of gold clusters. However, for AuNCs with a low Au/S ratio, the system prefers a ring motif rather than a longer staple motif, and the ring motif plays an important role in stability of the cluster because of the strong interaction with the Au core. For example, Au15(SR)13,34 Au22(SR)1835 Au20(TBBT)16,36 with a low Au/S ratio as 1.15, 1.22, 1.25, respectively, all contain a ring motif in the structure. The ring motif is reasonably consisted in the composition of Au29(SCH3)27 with the Au/S ratio of 1.074. After that, we used the "divide and protect"37 method to analyze the remaining structure. The size of the gold core in the cluster decreases as the Au/S ratio decreases. And the smallest gold


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core unit is Au4. Au29(SCH3)27 is similar to Au15(SR)13 in that it has a low ratio of Au/S and has two more gold atoms than sulfur atoms, so the gold core has the same size of Au4. And it is consistent with the results obtained by “divide and protected” calculation formula. So we get the structure of Au29(SCH3)27 consisting of two parts: a Ring protection unit (Part R) and an Au4 Core with a Staple motif structure (Part CS). Then we proposed different combination styles to isomers, and compared the energies of stable structures to discover a rule: For the isomers of N>6, (N is the number of Au atoms in the ring motif.) the Part R takes the form of two side chains that pass through Part CS, and for the isomers of N ≤ 6, the Part R takes the form of a longer side chain that passes through Part CS. The DFT calculation is performed on all isomers and the energies are ranked,

and

the

composition

of

the

lowest

energy

isomer

(isomer

1)

is

Au7(SCH3)7+Au4Au8(SCH3)9Au10(SCH3)11. Later, we calculated the electronic structure and optical properties of isomer 1. The HOMOLUMO band gap is 2.124 eV. In addition, we calculated the ultraviolet-visible (UV-vis) absorption spectrum by time-dependent density functional (TDDFT), which is found to be in good agreement with the experimental one. The above results provide the detailed atomic structure of a new ligand coated Au29(SG)27.

2. COMPUTATIONAL METHOD Through a lower Au/S ratio, we speculated that the structure of Au29(SCH3)27 contains a ring protection unit, and then used the "divide and protect" method to divide the structure and determine that the size of gold core is Au4. The initial structures were constructed using Gauss View 5.0, and the geometry structures of all isomers were optimized by DFT calculations. The commutative terms were processed by the generalized gradient approximation (GGA)38 with the Perdew-Burke-


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Ernzerhof (PBE) functional39. The LANL2DZ basis group was used for all Au atoms, and the 631G(d) basis group is used for C, H, and S atoms. The TDDFT was used to calculate the UV-vis absorption spectrum of the cluster, and the lowest 360 singlet to singlet excitation energies were calculated. All DFT, TDDFT and HOMO-LUMO energy gap calculations were calculated using the Gaussian 09 software package.40 The structure framework pictures of isomer were drawn by VEAST 3.3.0. The frontier molecular orbital composition picture and the UV-vis spectrum were drawn using Origin 8.

3. RESULTS AND DISCUSSION 3.1. To Determine the Size of the Ring Motif (Part R) and the Gold Core by Au/S Ratio. It is clear that there are 29 gold atoms and 27 sulfur atoms in Au29(SCH3)27, and the Au/S ratio is 1.074, which is close to 1. The minimum Au/S ratio is 1 in AuNCs, such as Au10(SR)1041 and Au12(TBBT)12,42 which contains two pentameric rings and two hexamer rings, respectively. Similarly, a ring motif is found in the structure of AuNCs with the Au/S ratio is slightly larger than 1. As we know, the Au/S ratio of Au15(SR)13,34 Au22(SR)1835, Au20(TBBT)16,36 is 1.153, 1.22 and 1.25, respectively. And the above structures contain Au5(SR)5, Au6(SR)6, Au8(SR)8 and ring motifs, respectively. As the size decreases, the surface curvature of the nanoclusters increases, so it is common to find gold-thiolate ring in smaller AuNCs. Therefore, it is speculated that similar ring motif exists in our system. As a part of the protective ligand, the ring motif has a strong interaction with the rest structure. If it is too large, the interaction is weakened because of the large internal space. If it is too small, the ring structure cannot be maintained. Therefore, we chose N=310 (N is the number of Au atoms in the ring motif) based on experience and reference to previous literature above. The “divide and protect” method has been proved to be in good agreement with


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the experiment in terms of structure separation43-45. So we took this method to divide the structure for the Part CS. The Part R and Part CS are shown in Table S1 of the supporting information. We know that for small-sized AuNCs with a low Au/S ratio, the closely packed tetrahedral Au4 is the basic structural unit of the gold core.46 In addition, according to the “divide and protect” method, we can also determine the size of the gold core. For Aun(SR)m, the general structure is divided into [Au]a+a'[Au(SR)2]b[Au2(SR)3]c[Au3(SR)4]d..., where a, a', b, c, d…are integers. [Au]a+a' is the Au core, and b, c, d … represent the number of staple motifs of different lengths. We expanded Part CS by this equation. For different Part CS, the Au atom is always two more than the S atom, and by calculation and analysis, the equation a+a'/2=2 is obtained. Then a' can only take an even number, so the gold core can only be an Au4, and all atoms are on the surface. (The calculation details are in section 2 of the supporting information) Due to the difference of Part R, we obtained a total of 51 isomers of Au29(SCH3)27. The specific structures are shown in Table 1.

Table 1. Specific Different Structural Divisions of Au29(SCH3)27 Part Ra

Part CSb

Part R

Au4[Au11(SCH3)12]2 Au4Au10(SCH3)11Au12(SCH3)13 Au3(SCH3)3

Au4(SCH3)4

Part CS Au4Au6(SCH3)7Au12(SCH3)13

Au7(SCH3)7

Au4Au5(SCH3)6Au13(SCH3)14












Au8(SCH3)8







7


Au5(SCH3)5

Au4[Au10(SCH3)11]2



Au4[Au8(SCH3)9]2






Au6(SCH3)6

Au9(SCH3)9









Au4Au(SCH3)2Au15(SCH3)16


Au4Au7(SR)8Au8(SR)9




Au7(SCH3)7

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Au10(SCH3)10


Au4[Au9(SCH3)10]2






aPart

R represents the Ring motif part, bPart CS represents the Au4 Core and Staple motif structure.

3.2 To Optimize the Geometrical Structures Through Various Combination Styles. 3.2.1 To Construct Different Combination Styles for Each N (N=3-10). Part R and Part CS are basic building blocks in atomic structure of Au29(SCH3)27. The interaction between the gold core and the ligand mainly affects the overall structural configuration, so the Part R is as close as possible to the gold core in the atomic structure combinations. The initial configurations of the Part R and Part CS are both outstretched and have enough internal space between them. So we considered whether the Part R passes through the staple motifs on both sides of the Au4 core to compact the overall structural configuration. Then, we proposed four combination styles for each N (N is the number of Au atoms in Part R) shown in Figure 1 as: (a) The first combination style:


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the Part R goes through the smaller staple motif; (b) The second combination style: the Part R goes through the larger staple motif; (c) The third combination style: the Part R goes through both staple motifs with crossing the gold core; (d) The fourth combination style: the Part R goes through neither staple motif with crossing the gold core.

Figure 1. Four different combination styles of Au29(SCH3)27 (Take a case of N=7 as an example). The Au-S framework is indicated by a ball-and-stick model with the same radius. The ring motif (Part R) is highlighted in green, and the gold core is highlighted in yellow (the C and H atoms are omitted).

3.2.2 To Choose the Optimized Combination Style for Each N. To clarify which one of the four combination styles is optimal with reduced calculation cost, we calculated the energy of partial isomers through above four combination styles by using DFT. We selected isomers based on the symmetry of the ligands on both sides of the gold core and the size of the Part R. Considering the size of the Part R, we chose the isomers of N=5,6,7,9. Then considered the symmetry of the ligands connected to the gold core, and selected the isomers of the same length and different lengths on both sides for calculation. The calculation results are shown in the Table S2 of supporting information. From the table, we can see that the isomers of N = 7 and 9 show better regularity, that is,

the

third

combination

has

the

lowest

energy.

Then,

an

isomer

as

Au8(SCH3)8+Au4Au7(SCH3)8Au10(SCH3)11 is randomly selected for calculation and verification.


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Therefore, the third combination is selected for optimization of isomers with N>6 in Part R. While for the isomers with N=5, 6, most of them have a low energy in the second combination style. So, when N≤6, the second combination style is selected for optimization. 3.2.3 To Optimize Each Structure by the Best Combination Style. In order to save the calculation cost, we chose the best combination style according to the rules obtained above to optimize the structures of all isomers and rank the energies. The energies of all the isomers that have reached stability are ordered in Table S3 (See Supporting Information for details). 3.2.4 To Confirm the Rationality of the Above Methods. We verified the above idea in two aspects. On one hand, we considered the case where the Part R was not included in the structure. We divided the overall structure of Au29(SCH3)27 by using “divide and protect” method, and obtained three isomers. Then we calculated their energies using DFT (shown in Table S4). The results show that the energy is higher than that of the isomer containing the Part R (Table S3). This reflects the atomic structure without ring motif perform less stability, so it is reasonable to include a ring motif in the structure of Au cluster with a smaller Au/S ratio. On the other hand, we considered the case where the Part R and Part CS were separately optimized firstly and then were combined together for overall optimization (Method S). We selected five different isomers randomly for comparison studies. The energies of stable structures obtained by Method S are found to be higher than that obtained by directly combined for optimization (Method D) as shown in Table S5. In Figure 2, we summary all the relative energies of stable Au29(SCH3)27 isomers to find the optimized Au29(SCH3)27 structure globally. The isomer 1 with the lowest energy contains ring motif and staple motifs of similar size. Moreover, there are different degrees of deformation in Part R and Part CS because of the Au-Au interaction between them.


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Figure 2. Relative energies of isomers of Au29(SCH3)27 at the PBE/GGA level of theory. The green, red, blue, dark cyan, magenta, violet, cyan, wine represent the relative energies of isomers contain the ring staple motifs of Au3(SCH3)3, Au4(SCH3)4, Au5(SCH3)5, Au6(SCH3)6, Au7(SCH3)7, Au8(SCH3)8, Au9(SCH3)9, Au10(SCH3)10. The pink represents the relative energies of isomers without ring motifs. The black and dark yellow represent the isomers by Method S. The structures of each color are drawn according to the energy from low to high.

3.3 To Illustrate the Atomic and Electronic Structure of the Optimized Au29(SCH3)27. It can be seen from Table S3 and Figure 2 that the three isomers with lower energy are Au7(SCH3)7+Au4Au8(SCH3)9Au10(SCH3)11,

Au6(SCH3)6+Au4Au7(SCH3)8Au12(SCH3)13,

Au7(SCH3)7+Au4Au4(SCH3)5Au14(SCH3)15. The structures of these three isomers are shown in Figure 3 with energy as 0 eV, 0.108 eV and 0.114 eV respectively. The atomic structures are indicated in diagram (a), (c) and (e). The corresponding framework structures are indicated in diagram (b), (d) and (f). To confirm the relative energy order of isomers, we introduced additional function and basis group as TPSS and 6-311(G) for C, H, S atoms/LANL2MB for Au atoms (noted as basis group 2), respectively. Together with PBE function and 6-31(G) for C, H, S atoms/LANL2DZ for Au atoms (noted as basis group 1), we compared the relative energies of


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isomer 1, isomer 2 and isomer 3 by setting PBE+ basis group 1, TPSS+ basis group 1 and PBE+ basis group 2 in Table S6 of the supporting information. As a result, the isomer 1 remains the lowest energy as the most optimized geometry after confirmation. And the Part R Au7(SCH3)7 of isomer 1 generally presents a chair configuration. In isomer 1, the average bond length of 54 AuS bonds is 2.379 Å, the average bond angle of 27 Au-S-Au angles is 100.13 °, and the average bond angle of 25 S-Au-S angles is 172.91 °. In addition, taking into account the ligand effect and further confirming the rationality of the ligand simplification, we changed back one -SG ligand (noted as confirmation 1) and all -SG ligands (noted as confirmation 2) of the ring motif for re-optimization on the isomer 1 of Au29(SCH3)27 as Figure S1 and Figure S2 show. Then we checked the root mean square deviations (RMSDs) of Au-S backbone structures between the isomer 1 geometry and the re-optimized geometry in both confirmation 1 and confirmation 2. The specific RMSDs are 1.537 Å and 2.087 Å respectively which are below the threshold of confirmation change as 3.000 Å. Therefore, there is no drastic changes on isomer 1 by -SG ligand simplification. The details are in Section 8 of supporting information.


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Figure 3. The Au29(SCH3)27 isomer structures with three lowest energies. (a) and (b) are the atomic and framework structures of isomer 1. (c) and (d) are the atomic and framework structures of isomer 2. (e) and (f) are the atomic and framework structures of isomer 3. In (a), (c) and (e), Au atoms are in orange, S atoms are in yellow, C atoms are in gray and H atoms are in white. In (b), (d) and (f), the Part R is in green, the gold core is in yellow, and the staple motifs are in pink.

The atomic structure and electronic structure determine the optical properties of the thiolprotected gold cluster. We analysed the properties of the cluster by calculating the composition of the highest occupied orbit (HOMO) and the lowest unoccupied orbit (LUMO). The gap between HOMO and LUMO is 2.124 eV. The HOMO-LUMO gap is in the range of the semiconductor band gap. The large band gap indicates that the electronic transition is not easy to occur, and the system has high kinetic stability and low chemical reactivity as well as its lowest energy in all isomers. We also calculated the orbital energies from HOMO-9 to HOMO and from LUMO to LUMO+9 as shown in Table S7 of the supporting information. The analysis of the molecular


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orbital of Kohn-Sham (KS) is shown in Figure 4 (a). From the figure, we can see that the LUMO orbital is mainly contributed by the Au(6s6p) orbital, and the HOMO orbital is mainly contributed by the Au(5d) orbital. In addition, we also plotted the distribution of Au atomic orbitals for each KS level (Figure 4(b)). Among them, LUMO is mainly contributed by gold atoms in the gold core, while HOMO is mainly contributed by gold atoms in gold core and those in the Part R with the similar contribution percentage. The electron density map of the frontier molecular orbital is shown in Figure 5. The electron density of LUMO is concentrated near the Au4 core and is mainly composed of d orbitals. The electron density of HOMO is concentrated near the Au4 core and the Part R, and it is mainly composed of p orbitals. In general, the transition of electrons in the frontier molecular orbital is mainly from d→p, which is within gold core or between gold core and the ring motif. The results are consistent with those shown in Figure 4.

Figure 4. (a) KS orbital energy and composition of Au29(SCH3)27 isomer 1. (b) The relative contribution of gold atomic orbital in different KS molecular orbitals of Au29(SCH3)27 isomer 1.


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Figure 5. HOMO-LUMO frontier molecular orbital distribution of Au29(SCH3)27 isomer 1.

3.4 To Confirm Au29(SCH3)27 Structure by Comparing with the Experimental Measurement. To further confirm that isomer 1 is the most stable structure of Au29(SCH3)27, we calculated the UV-vis absorption spectrum of isomer 1 using TDDFT and compared it with the experiment (shown in Figure 6). The experimental UV-vis spectrum is in black from Ref.30, while the calculated one is in red. In the UV-vis absorption spectrum calculation of isomer 1, we drew spectrum of a total of 360 excited states. In the theoretically calculated absorption spectrum, there is a characteristic absorption peak at 337 nm. Obviously, the 337 nm peak corresponds to 3.680 eV. From Figure 4, we can find that the electronic transitions of 337 nm peak are involved from the Au5d in the Au core to Au6s6p in the staple motifs (HOMO-8 to LUMO+6) and from Au5d in the Au core to Au5d in the ring motifs (HOMO-6 to LUMO+7). The corresponding orbital energy diagram is shown in Figure S3 of supporting information. The calculated 337 nm peak is in agreement with the experimentally obtained absorption peak near 330 nm30 within the error tolerance. Therefore, it is proved that the theoretically predicted isomer1 is the reasonable atomic structure of Au29(SCH3)27, and its coordinates and Mulliken charges are given in the Section 11 of supporting information.


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Figure 6. Experimentally measured UV-vis absorption spectra (black) and calculated absorption spectra (red) by TDDFT of Au29(SG)27.

4. SUMMARY To determine the atomic structure of Au29(SG)27, we used a thiolated methyl group to instead the larger glutathione ligand as Au29(SCH3)27 for calculation cost consideration. According to the lower Au/S ratio in Au29(SCH3)27 and the “divide and protect” method, we determined that the structure contains a ring motif and Au4 core, and finally obtained 51 different isomers. In order to define the optimal combination style between the ring motif (Part R) and Au4 core with staple motif (Part CS), we optimized the isomer structures in four different combination styles. We got a rule by ranking the energies that when N≤6 (N is the number of Au atoms in the ring motif), the second combination style (the Part R goes through the larger staple motif) keeps the most stable


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configuration, and when N>6, the third combination style (the Part R goes through both staple motifs with crossing the gold core) keeps the most stable configuration. By comparing the energies of all stable isomers, we obtained the most stable structural composition as isomer 1 that is Au7(SCH3)7+Au4Au8(SCH3)9Au10(SCH3)11. The frontier molecular orbitals of isomer 1 were analysed in details. Furthermore, the UV-vis absorption spectra of Au29(SCH3)27 isomer 1 were calculated and found to be in good agreement with the experimental ones, indicating that isomer 1 is the most stable atomic structure for Au29(SCH3)27. Then the accurate atomic structure of Au29(SG)27 could be obtained after the -SG ligand effect confirmation, which will help its molecular design in the future biological applications.

ASSOCIATED CONTENT (Word Style “TE_Supporting_Information”). Supporting Information. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] Notes There are no conflicts to declare. ACKNOWLEDGMENT This work was supported by the National Natural Science Foundation of China (31571026, 21727817).


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Glutathione-Coated Au29(SG)27: Structural Determination Based on

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