A Journal of Accepted Article Title: Stereoselective nanozyme based on ceria nanoparticles engineered with amino acids Authors: Xiaogang Qu, Yuhuan Sun, Chuanqi Zhao, Nan Gao, and Jinsong Ren This manuscript has been accepted after peer review and appears as an Accepted Article online prior to editing, proofing, and formal publication of the final Version of Record (VoR). This work is currently citable by using the Digital Object Identifier (DOI) given below. The VoR will be published online in Early View as soon as possible and may be different to this Accepted Article as a result of editing. Readers should obtain the VoR from the journal website shown below when it is published to ensure accuracy of information. The authors are responsible for the content of this Accepted Article. To be cited as: Chem. Eur. J. 10.1002/chem.201704579 Link to VoR: http://dx.doi.org/10.1002/chem.201704579 Supported by 10.1002/chem.201704579 Chemistry - A European Journal COMMUNICATION Stereoselective nanozyme based on ceria nanoparticles engineered with amino acids Abstract: Stereoselectivity towards substrate is one of the most important characteristics of enzymes. Amino acids, as cofactors of many enzymes, play important roles in stereochemistry. Herein, chiral nanozymes were constructed by grafting a series of D- or Lamino acids on surfaces of ceria (cerium oxide) nanoparticles. We selected the most commonly used drug for combating Parkinson?s disease 3, 4-dihydroxyphenylalanine (DOPA) enantiomers as examples for chiral catalysis. Through detailed kinetic studies of eight amino acids modified cerium oxide nanoparticles (CeNP), we found that phenylalanine-modified CeNP was optimal for the DOPA oxidation reaction and showed excellent stereoselectivity towards its enantiomers. L-phenylalanine-modified CeNP showed higher catalytic ability for oxidation of D-DOPA while D-phenylalaninemodified CeNP were more effective to L-DOPA. Taken together, the results indicated that stereoselective nanozyme can be constructed by grafting nanozyme with chiral molecules. This work may inspire better design of chiral nanozymes. Chirality is one of the most important characteristics of living system. Biomolecules, such as amino acids, sugars, DNA and protein are chiral. Living systems are very sensitive to the chiral species, such as drugs, because the interaction between two chiral species is usually in an enantiospecific way.1 Increasing researches showed that the chiral selectivity is one of life?s distinctive biochemical signatures, is a prerequisite in many biological processes.2 Natural enzymes are innately chiral and always consist of Lamino acids (with the exception of glycine). Their catalytic activity is highly dependent on the steric configuration of substrate.3 For instance, natural nucleases can only cleave the phosphodiester bonds of natural DNA substrate. However, LDNA, as the enantiomer of natural DNA, cannot be digested by nucleases because of their nonnative chirality.4 Although bearing high catalytic activity and specificity, natural enzymes possesses some shortcomings, such as low stability, difficulty in preparation, sensitivity to environmental conditions.5 Recently, remarkable progress has been made in developing artificial enzyme, especially nanomaterial-based artificial enzymes (nanozymes), which have been widely applied in biosensing, immunoassays, [a] [b] Y. Sun, Dr. C. Zhao, Dr. N. Gao, Prof. J. Ren and Prof. X. Qu Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China. E-mail: firstname.lastname@example.org Y. Sun University of Science and Technology of China, Hefei, Anhui 230026, China Supporting information containing the experimental section and additional characterization is available from the Wiley Online Library or from the author cancer diagnostics and therapy, etc.6 In the field of nanozymes, most attention has been paid to improve enzymatic activity, 7 realize new catalytic reactions, construct novel multi-nanozymes and exploit their applications. However, few investigations involve the chiral selectivity of nanozymes. Various nanomaterials have been used as nanozymes to mimic natural enzymes. Metal oxide nanoparticles are of particular interests because of both their acid?base and redox properties.8 Cerium oxide nanoparticles (CeNP), is one of the most widely used metal oxide catalysts.9 CeNP have been reported to have multienzyme mimetic activity, including superoxide oxidase (SOD), catalase and oxidase. 10 This is probably related to the coexistence of both Ce3+ and Ce4+ on the surface, where the Ce3+ species is coupled with oxygen vacancies. In addition, the properties of CeNP could be controlled and tailored in predictable synthetic methods to satisfy requirements of specific functions.11 Perez and colleagues prepared CeNP with oxidase-like activity to achieve colorimetric or fluorigenic immunoassays.12 However, they did not refer to the chiral selectivity, which is the indigenous property of enzyme. In order to better imitate the natural enzymes, stereoselectivity would be an unnegligible factor. Scheme 1. Illustration of stereoselective catalytic oxidation of the DOPA enantiomers by the phenylalanine-modified CeNP. With the catalysis of CeNP@D-Phe, L-DOPA was oxidized more effecively into L-dopachrome. Conversely, D-DOPA was oxidized more effectively than L-DOPA with CeNP@L-Phe. Herein, we found that 3, 4-dihydroxyphenylalanine (DOPA), as the most commonly used drug for combating Parkinson?s disease,13 can be catalytically oxidized by CeNP. Then, we set This article is protected by copyright. All rights reserved. Accepted Manuscript Yuhuan Sun,[a,b] Chuanqi Zhao,[a] Nan Gao,[a] Jinsong Ren,[a] and Xiaogang Qu*[a] 10.1002/chem.201704579 Chemistry - A European Journal out to construct chiral artificial oxidase by using D- or L-amino acids as the coating agents to confer the stereoselective property on the CeNP (Scheme 1). Amino acids can be cofactors of natural enzymes, and the stereochemical relation between amino acids and substrates plays important roles.14 For a comprehensive understanding, D- or L-amino acids were used for our study, including nonpolar amino acids (phenylalanine (Phe), alanine (Ala) and tryptophan (Trp)), and polar amino acids (histidine (His), glutamic acid (Glu), arginine (Arg), lysine (Lys) and tyrosine (Tyr)). Among these kinds of amino acidmodified cerium nanoparticles (CeNP@AA) we studied, phenylalanine-modified cerium nanoparticles (CeNP@Phe) showed optimal enzymatic activity. More importantly, CeNP@Phe exhibited excellent stereoselectivity for DOPA enantiomers as well. CeNP@L-Phe showed higher catalytic ability for D-DOPA while CeNP@D-Phe were more effective to L-DOPA. The D- and L- stereoselectivity has been further studied and verified. Firstly, various amino acids-modified CeNP with oxidase-like activity were fabricated. Poly (acrylic acid)-coated CeNP were synthesized by an in situ procedure for the following modification. Transmission electron microscopy (TEM) images revealed the particle diameter about 4.3 nm with well uniform distribution (Figure 1A and Figure S1). Due to their small size, CeNP exhibited high surface to volume ratio which would profoundly benefit their enzymatic activity. CeNP were further examined by X-ray photoelectron spectroscopy (XPS) to determine the mixed oxidation states (Figure 1B).15 Next, various amino acids were respectively modified onto the surface of CeNP via an amidation approach. The Fourier transform infrared (FT-IR) spectroscopy showed an obvious vibration band around 1656 cm?1, which confirmed the formation of acylamide bonds (Figure 1C). The corresponding thermo gravimetric analysis (TGA) plot demonstrated the coverage of amino acids was comparable Figure 1. Materials characterization of cerium oxide-based nanoparticles. (A) TEM image of CeNP. The inset is magnification of one segment. (B) XPS analysis of CeNP. (C) FT-IR spectra of CeNP and its derivatives. (D) XRD patterns of CeNP and CeNP@Phe. (Figure S2). Powder X-ray diffraction (XRD) patterns of CeNP@AA matched exactly to that of CeNP (Figure 1D), supporting the unspoiled crystal structure. We next evaluated the oxidase-like activity of the CeNP towards DOPA. As promising candidates, CeNP could catalytic oxidation of various organic substrates including 3, 3?, 5, 5?tetramethylbenzidine (TMB), 2, 2-azinobis (3ethylbenzothizoline-6-sulfonic acid) (ABTS) and dopamine.12a Based on UV-vis absorption measurements, the oxidation of DOPA was proved by the appearance of absorbance at 475 nm.16 Simultaneously, the obvious colour change from colourless to brown also demonstrated the oxidation of DOPA (Figure 2A). These experiments confirmed that CeNP could catalyze the oxidation of DOPA to dopachrome. It should be noted that CeNP acted as multivalent or cooperative catalysts, which was confirmed by the departure from linearity between initial rates versus concentration of CeNP (Figure S3).17 As shown in Figure 2B, after modified with amino acids, CeNP decreased the catalytic activity for DOPA to some extent. These results were understandable because some active sites of CeNP have been shielded by amino acids. Subsequently, we attempted to screen the optimal amino acids for constructing the stereoselective nanozyme through DOPA oxidation. Nonpolar amino acids (Phe with aromatic side chain, Ala with alkyl side chain), and polar amino acids (His with alkaline side chain, Glu with acid side chain) were modified respectively onto the surface of CeNP at first. By monitoring the absorbance change at 475 nm, the catalytic oxidation of DOPA by each of CeNP@AA was Figure 2. (A) UV/Vis spectra of CeNP (black line) and the oxidation of LDOPA in the absence (red line) and presence (blue line) of CeNP. The spectrum was monitored after 2 min. The inset shows the color change of CeNP after adding DOPA. (B) Saturation curves corresponding to the oxidation rate of DOPA to dopachrome at variable concentrations of D-DOPA, in the absence and presence of CeNP, CeNP@Phe, CeNP@His, CeNP@Ala, CeNP@Glu, respectively. The concentration of nanoparticles was 15 ?g/mL. The error bars represented the standard deviation of three measurements. (C) Schematic representation of different active energies of DOPA oxidation with various CeNP@AA. (D) The integration trends of Vmax and Ea of DOPA oxidation with CeNP@AA. Ea was in black line and boxes. Vmax was in red line and circles. This article is protected by copyright. All rights reserved. Accepted Manuscript COMMUNICATION 10.1002/chem.201704579 Chemistry - A European Journal examined (Figure S4). We observed that all CeNP@AA showed typical saturation kinetics (Figure 2B). Corresponding data were analysed in terms of the Michaelis?Menten model (Figure S4F and Table S2). Clearly, the different CeNP@AA differed in their catalytic performance. Among them, phenylalanine-modified cerium oxide nanoparticles (CeNP@Phe) revealed the highest catalytic efficiency towards DOPA. CeNP@His were also found to have a high catalytic activity. Yet CeNP@Glu showed the lowest catalytic performance. We inferred that the aromatic property (ie. Phe, His) and positively charged property (ie. His) of amino acids may be important factors for the high catalytic activity of CeNP@AA. We next investigated CeNP modified with several other amino acids, including tyrosine and tryptophan (aromatic amino acids), arginine and lysine (positively charged amino acids), to further optimize appropriate amino acids for the oxidation of DOPA (Figure S5). Clearly, aromatic amino acids modified CeNP had relatively higher catalytic activity and CeNP@Phe had the fastest catalytic rate. Next, On the basis of Arrhenius equation,18 the active energies of DOPA oxidation by various CeNP@AA were estimated (Figure 2C and Figure S6). Obviously, among them, CeNP@Phe had the lowest activation energy, which was in good agreement with its highest catalytic activity. To sum up the kinetic analyses (Figure 2D), CeNP@AA enabled function as a nanozyme, and CeNP@Phe were optimal for the oxidation reaction of DOPA. chiroselective performance of CeNP conjugated with phenylalanine enantiomers were examined, respectively (Figure S8). Based on Michaelis?Menten model, we analyzed and compared the kinetic parameters, which were summarized in Table 1. The Michaelis?Menten constant (Km) was estimated by Lineweaver?Burk plots (Figure S9). The smaller Km, the higher binding affinity between enzymes and substrates. 19 Catalytic number (Kcat) indicates the ability of enzyme to catalyze one certain substrate.20 Kcat/Km is usually applied for describing the catalytic efficiency of one enzyme.21 With regard to CeNP@DPhe (Figure 3C), Kcat for L- and D-DOPA were 3.12�?3 s?1, and 1.94�?3 s?1 (Table 1), respectively, indicating the higher catalytic ability of CeNP@D-Phe for oxidizing L-DOPA than DDOPA. Moreover, a lower Km value was observed for L-DOPA than D-DOPA, implying the stronger binding affinity of CeNP@D-Phe for L-DOPA. In addition, Kcat/Km of CeNP@D-Phe was higher for L-DOPA than D-DOPA, implying that CeNP@DPhe had higher catalytic efficiency (1.87 fold difference) for LDOPA than D-DOPA. These results would be discussed in detail in the following section. Accordingly, as contrast, the catalytic efficiency of CeNP@L-Phe for DOPA enantiomers was also studied and just a 1.13 fold difference was observed (Figure 3D and Table 1), indicating that, compared with CeNP@D-Phe, CeNP@L-Phe exhibited a weaker stereoselectivity for DOPA enantiomers. Beside CeNP@D-Phe, CeNP@D-His was also found to have obvious stereoselectivity. However, the trend of stereoselectivity was different from that with CeNP@D-Phe. CeNP@D-His exhibited higher catalytic ability for D-DOPA. (Figure S10 and Table S3). On the basis of the above results, modification of amino acids endowed nanoceria with stereoselectivity and its stereoselectivity was related to the chirality of the amino acid. Table 1. Kinetic Parameters for catalytic oxidation of DOPA enantiomers by CeNP@D-Phe and CeNP@L-Phe. Nanoenzyme [a] CeNP@L -Phe Figure 3. (A) The time-dependent absorbance changes of DOPA at 475 nm in the absence or presence of CeNP. (B) The absorbance change of DOPA enantiomers with CeNP@L-Phe, CeNP@D-Phe at 100s intervals. Saturation curves for the enantiomers of DOPA catalytic oxidation by CeNP@D-Phe (C), CeNP@L-Phe (D). All reactions were carried out in citric acid (25 mM) buffer, 45 癈. Error bars represent standard deviations of measurements (n = 3). Subsequently, we discussed the catalytically stereoselectivity of CeNP@AA towards DOPA enantiomers. The unmodified CeNP did not show any chiral selectivity for oxidation of L- and D-DOPA (Figure 3A), implying that the unmodificated nanozyme did not hold stereoselectivity. Howbeit the modification of amino acids could lead the difference for the oxidation of DOPA enantiomers (Figure S7). Therein, CeNP@Phe displayed relatively high stereoselective (Figure 3B). Thus, the catalytic CeNP@D -Phe Substrate D-DOPA L-DOPA D-DOPA L-DOPA Km Kcat (10-3 (?M) s-1) 0.424� 0.005 0.431� 0.004 0.195� 0.003 0.168� 0.004 Kcat/Km (10-3 s-1 M-1) 4.63�02 10.9 4.16�03 9.65 1.94�04 9.96 3.12�03 18.6 Selectivity factor[b] 1.13 1.87 [a] The concentration of nanozymes was calculated on the basis of the total mass of the Ce metal. The Ce content in these mimetic enzymes was determined by ICP analysis (see Table S1). [b] Selectivity factor of CeNP@L-Phe equals [Kcat/Km]D-DOPA/[Kcat/Km]L-DOPA. Selectivity factor of CeNP@D-Phe equals [Kcat/Km]L-DOPA/[Kcat/Km]D-DOPA. Each standard deviation was calculated from three measurements. For further understanding the different stereoselectivity, the molecular docking between different amino acids and DOPA was carried out with Discovery Studio 2.0 using CDdock protocol.22 As shown in Figure 4, both DOPA enantiomers can This article is protected by copyright. All rights reserved. Accepted Manuscript COMMUNICATION 10.1002/chem.201704579 Chemistry - A European Journal COMMUNICATION towards oxidation of L-DOPA than that of D-DOPA. In contrast, CeNP@L-Phe had higher oxidation ability for D-DOPA. Our results indicated that stereoselective nanozyme can be constructed by grafting nanozyme with chiral molecules. This work may inspire better design of chiral nanozymes. To this end, for example, peptide, nucleic acids and saccharide are promising cofactors23 for developing stereoselective nanozymes. Acknowledgements This work was supported by the 973 Project (2012CB720602), and NSFC (21210002, 21431007, 21533008, 21572216). Keywords: stereoselectivity ? nanozymes ? ceria nanoparticles ? amino acids ? DOPA         Figure 4. Energy-minimized average interaction models of (A) D-Phe with LDOPA, (B) D-Phe with D-DOPA, (C) L-Phe with D-DOPA and (D) L-Phe with L-DOPA. These complexes were shown in ball-and-stick model. Carbon atoms were indicated in black balls, hydrogen atoms were in gray, oxygen atoms were in red, while blue balls defineed nitrogen atoms. ?-? aromatic packing interaction was shown by a henna dash, and hydrogen bonds were shown by green dashes. In summary, we successfully prepared a stereoselective artificial oxidase based on CeNP and chiral amino acids. The active centre of this nanozyme is CeNP, while amino acids act as chiral recognition sites for DOPA. Among eight amino acids we studied, CeNP@D-Phe showed higher catalytic activity    a) H. Caner, E. Groner, L. Levy and I. Agranat, Drug Discovery Today, 2004, 9, 105-110; b) Y. Xia, Y. Zhou and Z. Tang, Nanoscale, 2011, 3, 1374-1382; c) J. Zheng, Y. Wu, K. Deng, M. He, L. He, J. Cao, X. Zhang, Y. Liu, S. Li and Z. Tang, ACS Nano, 2016, 10, 8564-8570. a) M. A. Mateos-Timoneda, M. Crego-Calama and D. N. Reinhoudt, Chem. Soc. Rev., 2004, 33, 363-372; b) M. Zhang, G. Qing and T. Sun, Chem. Soc. Rev., 2012, 41, 1972-1984; 3) S. 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This article is protected by copyright. All rights reserved. Accepted Manuscript COMMUNICATION 10.1002/chem.201704579 Chemistry - A European Journal COMMUNICATION COMMUNICATION Yuhuan Sun, Chuanqi Zhao, Nan Gao, Jinsong Ren and Xiaogang Qu* Page No. ? Page No. Stereoselective nanozyme based on ceria nanoparticles engineered with amino acids Accepted Manuscript Stereoselective artificial oxidase is constructed by grafting chiral amino acids on surfaces of cerium oxide nanoparticles. Among eight kinds of amino acids we studied, phenylalanine-modified CeNP is optimal for the DOPA oxidation reaction and show excellent stereoselectivity towards its enantiomers. This article is protected by copyright. All rights reserved.