Facile Fabrication of Magnetic MetalâOrganic Framework Nanofibers

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Facile Fabrication of Magnetic Metal-Organic Framework Nanofibers for Specific Capture of Phosphorylated peptides Weiwei Huan, Mingyang Xing, Chao Cheng, and Jie Li ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.8b04928 • Publication Date (Web): 20 Dec 2018 Downloaded from http://pubs.acs.org on January 3, 2019

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ACS Sustainable Chemistry & Engineering

Facile Fabrication of Magnetic Metal-Organic Framework Nanofibers for Specific Capture of Phosphorylated peptides Weiwei Huan,† Mingyang Xing,§ Chao Cheng,⊥ and Jie Li*†‡

†

Zhejiang Provincial Key Laboratory of Chemical Utilization of Forestry Biomass, Zhejiang A

＆F University, No. 666 Wusu Street, Lin’an District, Hangzhou 311300, P. R. China ‡

Zhejiang Provincial Collaborative Innovation Center of Agricultural Biological Resources

Biochemical Manufacturing, No. 318 Liuhe Road, Hangzhou 310023, P. R. China §

Key Laboratory for Advanced Materials and Institute of Fine Chemicals, School of Chemistry

& Molecular Engineering, East China University of Science and Technology, No. 130 Meilong Road, Shanghai 200237, P. R. China ⊥ The Department of Nuclear Medicine, Changhai Hospital, No. 168 Changhai Road, Shanghai 200433, P. R. China

* Corresponding Author. E-mail: [email protected]; Tel: 0086-571-63732772; Fax: 0086-571-63732772.

KEYWORDS:

nanowire,

nanofiber,

metal-organic

framework,

phosphorylated peptide enrichment, mass spectrum

ACS Paragon1112 Plus Environment

magnetic

separation,

ACS Sustainable Chemistry & Engineering 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ABSTRACT: A kind of magnetic metal-organic framework (mag-MOF) nanofibers was presented, the inorganic hydroxyapatite nanowires functionalized with magnetic nanoparticles on the surface acted as the scaffolds and templates for directed assembly of MIL-100(Fe) nanocrystals (one typical MOF). The as-prepared mag-MOF nanofibers have a porous structure, high specific surface area (403.6 m2 g-1), high pore volume (2.14 cm3 g-1), good hydrophilicity (a water contact angle of 0o), and unique magnetic response property (4.83 emu g-1). With these favourable characters, the mag-MOF nanofibers exhibited high affinity capability in the specific capture of phosphorylated peptides. The mag-MOF nanofibers exhibited high selectivity (a molar ratio of bovine serum albumin digest and β-casein digest of 500:1), high detection sensitivity (0.5 fmol), desirable capture recovery (87.79 %), high capture capacity (93.8 mg g-1) and good repeatability. Moreover, the practical applications of mag-MOF nanofibers in the selective separation and identification of phosphorylated peptides in complex biological specimens (nonfat milk digest, human serum, and human saliva) were realized. Additionally, a continuous filtering approach was proposed for phosphorylated peptide enrichment through the mag-MOF nanofiber-based membrane. The present research provides a versatile strategy for the construction of several kinds of functional MOF nanofibers with different immobilized metal ions for the selective capture and identification of targeted biomolecules.

INTRODUCTION Selective capture and identification of targeted biomolecules from complex biological specimens is a significant topic in biomedical researches.1 Protein phosphorylation regulates several biological procedures, such as immune response, signal transduction, and enzymatic activity.2-3 Comprehensive analysis and identification of phosphorylated biomolecules are available for the in-depth understand of biological processes and discovery of potential disease biomarkers. Nevertheless, it is still a huge challenge for the direct characterization of phosphorylated peptides using the mass spectrometry (MS) method due to the low concentrations


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of phosphorylated peptides in specimens and the serious signal interference from high concentrations of non-phosphorylated peptides.4-5 Thus, an effective enrichment approach for the specific separation of phosphorylated peptides from biological specimens is highly imperative. Until now, numerous strategies and affinity materials have been developed to fulfill the requirements in phosphorylated peptide enrichment and identification.6-7 The most effective approach is take advantage of the strong interactions between phosphates and metal ions, as realized in metal oxide affinity chromatography (MOAC)8-10 and immobilized metal ion affinity chromatography (IMAC).11-13 A series of IMAC materials with different immobilized metal ions were applied in phosphorylated peptide enrichment.14-17 These results have revealed that an IMAC bead with a porous structure, a large specific surface area and high amount of binding sites was beneficial to improve the phosphorylated peptide capture efficiency.5,

17-20

As a

promising type of porous material, metal-organic frameworks (MOFs) have extraordinary surface area, uniform and controllable porosity, high functional tunability, and abundant active site.21-22 In addition, in combination with the specific interactions between unsaturated metal ions and peptides or proteins, MOFs exhibited high enrichment abilities toward targeted biomolecules in proteomic researches.23-29 In the sample pre-treatment processes using MOFs as the sorbents, centrifugation at high speed or filtration operation is indispensable during the separation period, which is not only troublesome, but also may causes sample loss and low detection sensitivity for low-abundant biomolecules. As one of the charming materials, magnetic nanoparticles have attracted great interests in sample pre-treatment fields because of the rapid response and separation under an external magnetic field.30-31 So far, several types of magnetic MOFs have been fabricated and applied in phosphorylated peptide enrichment.32-36 Nevertheless, the relatively low specific surface area, and low content of MOF component may limit the enrichment efficiency and enrichment capacity. On the other hand, the majority of magnetic MOF composites were simply spheres with the core-shell structure and the diameter of several nanometers at present.



Additionally, the multiform morphology of affinity material might influences the capture capacity and detection sensitivity in phosphorylated peptide enrichment to some extent. Therefore, the development of magnetic MOF materials with controllable and appointed morphologies is still attracting research attention in phosphoproteome research. In this study, a kind of magnetic MOF (mag-MOF) nanofibers was developed. Inorganic hydroxyapatite nanowires functionalized with magnetic nanoparticles on the surface were employed and acted as the scaffolds and templates for directed the controllable assembly of MOF nanocrystals (i.e MIL-100(Fe)). The mag-MOF nanofibers exhibited several distinct advantages: Firstly, the hydroxyapatite nanowires have abundant active sites on the surface, the magnetic nanoparticles and MOF nanocrystals can be deposited on the surface, which avoids the tedious surface modification with organic linkers. Secondly, the large specific surface area, and relatively high content of MOF component contribute to the improved capture efficiency and capture capacity. Thirdly, the magnetic response ability simplifies the separation process. With these favourable characters, the as-prepared mag-MOF nanofibers showed high selectivity, high detection sensitivity, desirable capture recovery, large capture capacity, and good repeatability. Moreover, the successful applications of mag-MOF nanofibers in the selective capture of phosphorylated peptides from practical biological specimens including non-fat milk digest, human serum and human saliva were demonstrated.

EXPERIMENTAL SECTION Chemicals and materials. Iron (III) acetylacetonate, iron (III) chloride hexahydrate, and benzene-1,3,5-tricarboxylic acid were obtained from Aladdin Industrial Co., Ltd (Shanghai, China). α-casein, β-casein, trypsin, bovine serum albumin (BSA), dithiothreitol, iodoacetamide, sodium bicarbonate, and concentrated ammonia aqueous solution (NH3·H2O, 28―30 wt %) were received from Sigma-Aldrich (St, Louis, MO, USA). Non-fat milk was bought from a native


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shop. The healthy human serum was received from a local hospital. Acetonitrile (MeCN) and trifluoroacetic acid (TFA) were purchased from Merck (Darmstadt, Germany). Oleic acid, calcium chloride, sodium hydroxide, sodium dihydrogen phosphate dehydrate, triethylene glycol, and ethanol were received from Sinopharm Chemical Reagent Co., Ltd (Shanghai, China). Pure water was produced by a Milli-Q system (Millipore, Milford, MA, USA). Preparation of mag-MOF nanofibers. The mag-MOF nanofibers were fabricated by a three-step process. Firstly, inorganic hydroxyapatite nanowires acted as the scaffolds were synthesized through a solvothermal approach.37-39 In detail, 100 g of oleic acid and 140 g of ethanol were mixed together. Then, 2.20 g of calcium chloride in 200 mL of water, 10.0 g of sodium hydroxide in 200 mL of water, and 2.80 g of sodium dihydrogen phosphate dehydrate in 100 mL of water were poured into the mixture in sequence under vigorous agitation. The mixture was reacted in a 1 L autoclave for 24 h at 180 oC. After natural cooling down to 20―30 oC, the obtained HAP nanowires were washed with ethanol and water. Subsequently, the hydroxyapatite nanowires were functionalized with magnetic nanoparticles on the surface. Specifically, 1.0 g of hydroxyapatite nanowires and 0.5 g of Iron (III) acetylacetonate were dispersed in 180 mL of triethylene glycol. The mixture was poured into a 1 L autoclave, and heated for 12 h at 220 oC. The obtained product of mag-HAP nanowires was washed with water and ethanol. Furthermore, a layer-by-layer approach was employed for the formation of MOF nanocrystals on mag-HAP nanowires. Briefly, 400 mg of mag-HAP nanowires were alternately dispersed in the benzene-1,3,5-tricarboxylic acid solution (40 mL of ethanol, 10 mmol L-1) at 60 oC for 30 min and an iron (III) chloride hexahydrate solution (40 mL of ethanol, 10 mmol L-1) for 15 min at 60 oC. At each cycle, the intermediates were centrifugally separated at 4000 rpm for 3 min, and washed with ethanol solution for two times. After repeating for 30 cycles, the as-prepared mag-MOF nanofibers were dried at 150 oC for 12 h. Moreover, the layer-by-layer procedure was



repeated for 10 and 20 cycles, respectively, and the corresponding products were marked as magMOF-10 and mag-MOF-20. For comparison, the core-shell Fe3O4@MOF nanoparticles were also prepared according to the published researches.26, 34 For fabricating mag-MOF nanofiber-based membrane, 30 mg of obtained mag-MOF nanofibers were added to 30 mL of ethanol, and the suspension solution was filtered under the vacuum filtration process. The mag-MOF nanofiber-based membrane was obtained after being dried at 80 oC for 20 min. Preparation of biological specimens. 1 mg of α-casein or β-casein was added to 1 mL of sodium bicarbonate buffer at a concentration of 50 mmol L-1 and a pH value of 8.3, and digested with 20 μg of trypsin at 37 oC for 18 h. In addition, 2 mg of BSA was denatured at 60 oC

for 20 min in 1 mL of aqueous solution containing sodium bicarbonate buffer at a

concentration of 50 mmol L-1, urea at a concentration of 8 mol L-1, and a pH value of 8.3. Afterward, 20 μL of dithiothreitol at a concentration of 1 mol L-1 was added and incubated at 60 oC

for 1 h. Soon after, 7.4 mg of iodoacetamide was mixed and incubated at 25 oC for 1 h in

darkness. Finally, the treated BSA solution was added to 9 mL of sodium bicarbonate buffer at a concentration of 50 mmol L-1 and a pH value of 8.3, and digested with 20 μg of trypsin at 37 oC for 18 h. 20 μL of non-fat milk was dispersed in 1 mL of sodium bicarbonate buffer at a concentration of 50 mmol L-1 and a pH value of 8.3, and the sample was centrifugally separated for 3 min at 15000 rpm. The collected supernatant was treated in water with a temperature of 90―100 oC for 10 min. After cooled to 25―30 oC, 40 μg of trypsin was added and incubated at 37 oC for 18 h. Additionally, human serum or human saliva was diluted with 9-fold pure water, and stored at a refrigerator with a temperature of -20 oC. Selective capture of phosphorylated peptides. 200 μg of as-prepared mag-MOF nanofibers and a certain amount of α-casein digest or β-casein digest (with or without BSA


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digest) were added to 400 μL of MeCN-H2O-TFA solution (60:39:1, v/v/v). After gentle incubation at 25 oC for 15 min, the mag-MOF nanofibers were magnetically separated and washed with 400 μL of MeCN-H2O-TFA solution (60:39:1, v/v/v) for two times. Sequentially, 30 μL of NH3·H2O (10 wt %) was added, and the eluate was analysed by MALDITOF MS. In the enrichment procedure through the mag-MOF nanofiber-based membrane, a piece of small-sized mag-MOF nanofiber-based membrane was fixed in a filter container with an effective area of 1.13 cm2. The MeCN-H2O-TFA solution (60:39:1, v/v/v) containing tryptic digest was continuously pumped into the filter container, the flow rate was fixed at about 1 mL min-1. In addition, 1 mL of NH3·H2O (10 wt %) was used, the obtained eluate was freeze-dried and re-dissolved in 30 μL of MeCN-H2O solution (50:50, v/v), and analysed by MALDI-TOF MS. For the treatment of complex specimens, 400 μg of as-prepared mag-MOF nanofibers were incubated with human serum sample or human saliva or the digested peptides from non-fat milk in a 400 μL of MeCN-H2O-TFA solution (60:39:1, v/v/v) for 15 min. After the washing process, 30 μL of NH3·H2O solution (10 wt %) was added and the eluate was analysed by MALDI-TOF MS or nano-LC-MS/MS.

RESULTS AND DISCUSSION Preparation and characterization of mag-MOF nanofibers. The fabrication process of magMOF nanofibers was illustrated in Figure 1a. At first, hydroxyapatite (HAP) nanowires acted at the scaffolds were firstly synthesized. Afterward, Fe3O4 nanoparticles were immobilized on the surface of HAP nanowires to obtain the mag-HAP nanowires. Next, the assembly of MIL100(Fe) nanocrystals (one typical MOF) on the surface was achieved through a layer-by-layer process to fabricate the mag-MOF nanofibers. HAP nanowires were employed as the scaffolds and templates for the following advantages: the abundant active sites on HAP nanowires induced the immobilization of Fe3O4 nanoparticles and growth of MOF nanocrystals, avoiding the



tedious surface modification with organic linkers; the nanometre-sized diameters and high aspect ratios of HAP nanowires contributed to the formation of mag-MOF nanofibers composite with a large specific surface area and high content of MOF component, which may endowed the affinity material with numerous binding sites and improved performance in the specific capture of low concentrations of phosphorylated peptides.

Figure 1. Illustration of (a) the fabrication process of mag-MOF nanofibers, and (b) specific capture and magnetic separation of phosphorylated peptides using mag-MOF nanofibers.


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Figure 2. TEM images of (a) HAP nanowires, (b) mag-HAP nanowires, and (c, d) mag-MOF nanofibers. Inset shows the digital images of the corresponding power sample.

The morphology of as-prepared sample was characterized by TEM. In Figure 2a, the obtained HAP sample was composed of nanowires with an average diameter of about 20 nm and high aspect ratios as high as several hundred. In addition, different from the smooth surface of HAP nanowires, a plenty of small nanoparticles were deposited on mag-HAP nanowires (Figure 2b). The immobilized Fe3O4 nanoparticles exhibited a particle size of around 12 nm. The sample changed from white color to gray black color (digital images inset in Figure 2a, 2b), further revealing the actual immobilization of Fe3O4 nanoparticles. Moreover, after the formation of MOF nanostructure on the mag-HAP nanowires, the color and morphology of the material markedly changed. The sample displayed a yellow color, revealing the successful formation of mag-MOF nanofibers. Additionally, the core-shell structure was observed in the TEM image of mag-MOF nanofibers (Figure 2c, 2d). A uniform coating of MOF layer with an average thickness of approximately 50 nm was introduced to the surface of mag-HAP nanowires. It should be noted that the surface modification of organic linkers was unnecessary in this research. HAP nanowires have abundant Ca2+ ions on the surface, the organic building block, benzene-



1,3,5-tricarboxylic acid, could be chelated with inherent Ca2+ ions for subsequent LbL process. In the preparation procedures of other MOF composites,26, 32-36, 40-41 the first surface modification of organic linkers was an indispensable step. By contrast, the proposed approach in this study was more convenient, versatile, and low-cost.

Figure 3. (a) FTIR spectra and (b) TG curves: (i) HAP nanowires, (ii) mag-HAP nanowires, and (iii) mag-MOF nanofibers.


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FTIR spectroscopy was employed to check the chemical structure of HAP nanowires, magHAP nanowires, and mag-MOF nanofibers. The characteristic peaks of the hydroxyl group (3572 cm-1), PO43- group (561, 604, 962, 1030, and 1097 cm-1), and adsorbed water (3428 and 1635 cm1)

were discovered in Figure 3a. However, because of the typical absorption peak of Fe3O4 (560

cm-1)27 overlaps the characteristic peaks of PO43- group, the FTIR spectrum of mag-MOF nanowires has slight changed. Furthermore, several new peaks appeared in Figure 3c, the absorption peak at 1718 cm-1 corresponds to the C=O stretching vibration. In addition, the characteristic bands at 1575, 1448, and 1383 cm-1 were assigned to the benzene ring stretching vibration.42 All these results demonstrated the successful construction of mag-HAP nanofibers. TG analysis was performed to study the chemical component. The weight loss belonging to adsorbed water in mag-MOF nanofibers was 6.86 wt % (Figure 3b). In comparison, the weight loss comes from the decomposition of mag-MOF nanofibers was calculated to be 21.01 wt %, further proving the formation of MOF on the mag-MOF nanowires. The value of weight loss was higher than other magnetic MOF composites,26,

34

indicating the higher content of MOF

component in as-prepared mag-MOF nanofibers than that of other magnetic MOF composites. XRD analysis was conducted to characterize the structure. In Figure 4a, the diffraction peaks can be indexed to the standard data of hydroxyapaptite (JCPDS no. 09-0432).37 Additionally, the relatively enhanced intensity of a diffraction peak marked with rhombus at 2θ = 35.4o corresponds to the (311) crystal plane of Fe3O4 nanoparticles.43 Moreover, a low diffraction peak marked with asterisk at 2θ = 10.3o ascribes to the (428) crystal plane of MIL-100(Fe).44 These results indicated that the synthetic nanofibers comprising HAP, Fe3O4, and MIL-100(Fe).



Figure 4. (a) XRD patterns: (i) HAP nanowires, (ii) mag-HAP nanowires, (iii) and mag-MOF nanofibers; (b) Nitrogen adsorption-desorption curve of mag-MOF nanofibers, inset is the BJH pore-size distribution curve; (c) Magnetization hysteresis curves: (i) mag-HAP nanowires, and (ii) mag-MOF nanofibers; (d) the digital images of as-prepared mag-MOF nanofibers: (i) dispersed aqueous solution, (ii) magnetic separation, and (iii) the water contact angle.

The specific surface area, pore volume and pore size distribution were determined. The Brunauer-Emmett-Teller (BET) specific surface areas of HAP nanowires and mag-HAP nanowires were measured to be 27.9 and 34.0 m2 g-1, respectively (Figure S1a and S1b, Supporting Information). In comparison, the as-prepared mag-MOF nanofibers had a high BET


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specific surface area of 403.6 m2 g-1 (Figure 4b) and a pore volume of 2.14 cm3 g-1. According to the inner curve in Figure 4b, the mag-MOF nanofibers exhibited several types of mesoporous and macropore. The mesoporous pore (3.36 nm) was derived from the MOF nanostructure, while the relatively large mesoporous pore (40.3 nm) and macropore (63.4, 79.9, and 169.8 nm) may derived from the assembled mag-MOF nanofibers. The value of the BET specific surface area of mag-MOF nanofibers was higher than that of other magnetic MOF materials (Table S1, Supporting Information). Especially, the pore volume of mag-MOF nanofibers is amazingly high, the feature may benefited from the unique one-dimensional fiber structure and the self-assembly behaviour when mixed together. Importantly, the porous structure of affinity material would contribute to abundant binding sites, fast adsorption of targets, which were significant for highly specific capture of biological biomolecules with desirable performance. Another advantages of as-prepared mag-MOF nanofibers were the unique magnetic responsive property and good hydrophilicity. The curves in Figure 4c showed that the two materials have superparamagnetic properties. The saturation magnetization values of mag-HAP nanowires and mag-MOF nanofibers were measured to be 11.4 and 4.83 emu g-1, respectively. In addition, both the as-prepared mag-HAP nanowires and mag-MOF nanofibers displayed good hydrophilicity with water contact angles of 0o. Figure 4d shows the excellent dispersibility of as-prepared magMOF nanofibers in water. Moreover, benefit from the unique magnetic feature of Fe3O4 component, the as-prepared mag-MOF nanofibers can be rapidly agglomerated on the inner surface of the glass tube in twenty minutes with the help of a magnet (Figure 4d). Furthermore, the scalable synthesis of mag-MOF nanofibers can be realized. As a typical example, a dry weight of about 11 g of HAP nanowires was prepared in four reactors (Figure S2a, Supporting Information). After orderly loaded with Fe3O4 nanoparticles and coated with MOF component through the simple solvothermal process and layer-by-layer approach, about 10 g of mag-MOF nanofibers can be obtained in a batch of laboratory experiment (Figure S2b,



Supporting Information). This result demonstrated the scalable preparation of mag-MOF nanofibers, and it holds great promising potential for practical applications.

Application of mag-MOF nanofibers in specific capture of phosphorylated peptides from standard protein digests. In virtue of the porous feature, high specific surface area, large pore volume, unique magnetic property, and strong interactions between iron and phosphate groups, the as-prepared mag-MOF nanofibers were applied for the specific capture of phosphorylated peptides. A typical process was illustrated in Figure 1b. In brief, the as-prepared mag-MOF nanofibers were incubated with the protein digest. After magnetic separation and washing operation, the phosphorylated peptides were eluted and directly analysed by MALDI-TOF MS.

Figure 5. MALDI-TOF MS spectra: (a) direct analysis of 0.5 pmol of β-casein digest, (b) enriched by mag-MOF nanofibers, and (c) enriched by Fe3O4@MOF nanoparticles; the dephosphorylated peptides are labeled with # symbols.

-casein digest was first used to investigate the capture ability of as-prepared magMOF nanofibers. As can be seen from Figure 5a, only one phosphorylated peptide (1)


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peak was observed with low MS signal intensity and low signal-to-noise (S/N) ratio, and other phosphorylated peptides were strongly suppressed by the abundant nonphosphorylated peptides. In contrast, after enriched by mag-MOF nanofibers, the MS signals of non-phosphorylated peptide peaks were remarkably reduced, three targeted phosphorylated peptides (1, 2, and 3) and their dephosphorylated peptides with high S/N ratios could be clearly detected (Figure 5b). For comparison, Fe3O4@MOF nanoparticles (SEM image and pore properties are displayed in Figure S3, Supporting Information) were also employed to capture the phosphorylated peptides. However, three identified phosphorylated peptides (1, 2, and 3) exhibited the relatively low S/N ratios. For example, the S/N ratios of 1 were calculated to 4425 and 3069 in the MS spectra after enriched by mag-MOF nanofibers and Fe3O4@MOF nanoparticles, respectively. The mag-MOF nanofibers showed more superior capture performance. These results demonstrated that the high specific surface area and pore volume are propitious to high phosphorylated peptide capture capacity. This result may profited from the porous feature, high content of MOF component, and numerous binding sites for selective capture of phosphorylated peptides. The detailed information of the peptide sequence and m/z of the enriched phosphorylated peptides from -casein digest were shown in Table S2 (Supporting Information). To further investigate the specific enriching ability of as-prepared mag-MOF nanofibers for phosphorylated peptides, α-casein digest was employed. In Figure 6a, the non-phosphorylated peptide peaks occupied the MS spectrum and only one phosphorylated peptide (α7) peak could be detected. Fortunately, after enriched by magMOF nanofibers (Figure 6b) or Fe3O4@MOF nanoparticles (Figure 6c), the nonphosphorylated peptide peaks were effectively removed, the phosphorylated peptide peaks with high S/N ratios dominated the spectra. The enrichment ability of mag-MOF nanofibers was better than that of Fe3O4@MOF nanoparticles. For instance, the S/N ratios



of α7 were measured to 3307 and 2446 in the MS spectra after enriched by mag-MOF nanofibers and Fe3O4@MOF nanoparticles, respectively. The detailed information of the peptide sequence and m/z of the enriched phosphorylated peptides from α-casein digest were shown in Table S3 (Supporting Information). These results demonstrated the excellent capture specificity of as-prepared mag-MOF nanofibers for phosphorylated peptides.

Figure 6. MALDI-TOF MS spectra: (a) direct analysis of 0.5 pmol of α-casein digest, (b) enriched by mag-MOF nanofibers, and (c) enriched by Fe3O4@MOF microspheres; the dephosphorylated peptides are labeled with # symbols.

The high selectivity of the as-prepared mag-MOF nanofibers for enriching phosphorylated peptides was further examined. β-casein digest and BSA digest were mixed for the testing. As illustrated in Figure 7a, none phosphorylated peptide peak was detectable. Fortunately, after enriched by mag-MOF nanofibers, three targeted phosphorylated peptides and their dephosphorylated peptides with high S/N ratios were detected (Figure 7b). Moreover, even though the molar ratio of β-casein and BSA was


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raised to 1:500, three targeted phosphorylated peptides and their dephosphorylated peptides still could be obviously identified with almost no interference (Figure 7c). Obviously, this result demonstrated that the as-prepared mag-MOF nanofibers could specifically capture low concentrations of phosphorylated peptides.

Figure 7. MALDI-TOF MS spectra: (a) direct analysis of the peptide mixture containing β-casein digest (0.5 pmol) and BSA digest with a molar ratio of 1:100; (b, c) after treated by mag-MOF nanofibers when the molar ratios of β-casein digest and BSA digest were 1:100 and 1:500, respectively. The dephosphorylated peptides are labeled with # symbols.

Investigation of detection sensitivity, capture recovery, capture capacity, and repeatability of mag-MOF nanofibers. Because of the concentrations of targeted biomolecules in the biological specimens could be much low, the detection sensitivity is a critical evaluation parameter. Three different concentrations of β-casein digests were enriched with mag-MOF nanofibers, the captured phosphorylated peptides were eluted and analysed using MALDI-TOF MS, respectively. In Figure 8a, three phosphorylated peptide peaks could be observed with a highest S/N ratio of 904.1 (β1). Further decreasing the total amount of β-casein digest to 0.5 fmol



(Figure 8c), one phosphorylated peptide (β1) peak could still be identified with the S/N ratio of 19.7. The achieved detection limit was lower than these of many IMAC and OMCA materials (Table 1). The high detection sensitivity may be ascribed to the porous feature, high content of MOF component, numerous Fe3+ ion sites, specific affinity interactions, good hydrophilicity, and unique magnetic responsibility of as-prepared mag-MOF nanofibers. This result demonstrated that the mag-MOF nanofibers can be used for the capture of phosphorylated peptides at low concentrations. The capture recovery of mag-MOF nanofibers toward phosphorylated peptides was assessed using an isotope dimethyl labeling approach. As shown in Figure 9a, the capture recovery of mag-MOF nanofibers toward the standard phosphorylated peptide was as high as 87.79 %. The value was slight higher than other affinity materials (Table 1).

Figure 8. MALDI-TOF MS spectra of β-casein digest enriched by mag-MOF nanofibers. The three different concentrations are 50 fmol (0.5 μL) (a), 5 fmol (0.5 μL) (b), and 0.5 fmol (0.5 μL) (c), respectively, the dephosphorylated peptides are labeled with # symbols.


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The capture capacity of mag-MOF nanofibers toward phosphorylated peptides was studied. The binding capacity of mag-MOF nanofibers was determined to be 93.8 mg g-1. These results revealed that the porous structure, high specific surface area, high content of MOF component, and numerous Fe3+ ion sites on the as-prepared material greatly improved the enrichment capacity of mag-MOF nanofibers toward phosphorylated peptides.

Figure 9. (a) MALDI-TOF MS spectrum of a mixture contains a standard phosphorylated peptide labeled by two labeled by two

14CH

3

12CH

3

and the same amount of the standard phosphorylated peptide

after enriched with mag-MOF nanofibers, (b) Intensities of a

phosphorylated peptide (1) from -casein digest after enriched with different amounts of magMOF nanofibers.

The repeatability of as-prepared mag-MOF nanofibers was investigated. Three batches of mag-MOF nanofibers were severally applied to the selective capture of β-casein digest, and the results were shown in Figure S4 (Supporting Information). The RSDs of the peak heights of three targeted phosphorylated peptides were displayed in Table S4 (Supporting Information). The RSDs were calculated to below 10 %. This result showed the good repeatability of magMOF nanofibers in phosphorylated peptide enrichment.



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The effect of mag-MOF nanofibers with different content of MIL-100(Fe) on the capture capability for phosphorylated peptide is investigated. As revealed in Table S5 (Supporting Information), the BET specific surface area, pore volume, and weight loss in TG analysis results proved that the amount of MIL-100(Fe) increases almost linearly with increasing the layer-bylayer cycles. Soon after, the detection sensitivity, enrichment recovery, and binding capacity of mag-MOF-10, mag-MOF-20 and mag-MOF-30 in phosphopeptide enrichment were determined. The amount of MIL-100(Fe) on mag-MOF nanofibers has slight effect on the detection sensitivity and capture recovery. These results may contributed to the relatively enough binding sites on mag-MOF nanofibers for the selective enrichment of relatively small amount of phosphorylated peptides. However, the amount of MIL-100(Fe) strongly affects the binding capacity for phosphorylated peptide enrichment. The binding capacity was nearly linear with the amount of MIL-100(Fe). These results demonstrated that the enrichment performance of magMOF nanofibers strongly depended on the amount of MIL-100(Fe). Additionally, the excellent enrichment performance of mag-MOF nanofibers can be achieved by controlling the layer-bylayer cycles in material preparation procedure.

Table 1 Comparison of mag-MOF nanofibers and the reported materials for phosphorylated peptide enrichment Enrichment materials

Detection sensitivity

Capture recovery

Ref.

4 fmol

NG [a]

[17]

Fe3O4@MOF nanoparticles

0.5 fmol

84.47 %

[34]

Fe3O4@polydopamine-Ti4+

2 fmol

NG [a]

[45]

mesoporous γ-Fe2O3

50 fmol

89.4 %

[46]

Bone-like GdF3

80 fmol

NG [a]

[47]

Graphene@polydopamine@TiO2

5 fmol

86.70 %

[48]

Fe3O4@polydopamine-Nb5+

2 fmol

60 %

[49]

SPIOs@PVP-PEI@MOF@Arg

10 fmol

NG [a]

[50]

MG@mSiO2-ATP-Ti4+


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Mag-MOF nanofibers [a]

0.5 fmol

87.79 %

This work

Not given

Application of mag-MOF nanofibers in specific capture of phosphorylated peptides in practical biological specimens. Encouraged by the above experimental results, the magMOF nanofibers were further used for the selective capture of low concentrations of phosphorylated peptides in practical biological specimens. In Figure 10a, nonphosphorylated peptides dominated the MS spectrum of non-fat milk digest, and nearly no phosphorylated peptide peak can be observed. Fortunately, after enriched by magMOF nanofibers, 9 phosphorylated peptide peaks and their dephosphorylated peptides with relatively high MS signal intensities were distinctly observed (Figure 10b). The detailed information of the peptide sequence and m/z of the identified phosphorylated peptides from nonfat milk digest were displayed in Table S6 (Supporting Information). Similarly, for the human serum sample in Figure 10c, no phosphorylated peptide peak can be observed because of the strong interference of the high concentrations of nonphosphorylated peptides and high salt content. On the contrary, four phosphorylated peptides were clearly observed with high MS signal intensities (Figure 10d). The detailed information of the peptide sequence and m/z of the identified phosphorylated peptides from human serum were shown in Table S7 (Supporting Information). On the other hand, the human serum contains several types of high concentrations of proteins including albumin and immunoglobulins.51-52 In Figure 10e, three peaks of human serum albumin (67 KDa) detected in the MS spectrum. After treated with mag-MOF nanofibers, these peaks disappeared with a clean background (Figure 10f), which revealed the high enrichment selectivity of mag-MOF nanofibers toward phosphorylated peptides under the interferences of both abundant non-phosphorylated peptides and proteins.



Furthermore, we use the as-prepared mag-MOF nanofibers to capture the phosphorylated peptides in 5 μL of pristine human saliva sample, the collected eluent was analysed by nano LCMS/MS. In total, 31 phosphorylated peptides including 8 multi-phosphorylated peptides and 23 mono-phosphorylated peptides were identified. The detailed information of identified phosphorylated peptides in pristine human saliva is displayed in Table S8 (Supporting Information). The identified performance of as-prepared mag-MOF nanofibers is better than or compared to several MOF and other affinity materials.29,

53, 54

To sum up, all these results

demonstrated that the as-prepared mag-MOF nanofibers have practical application ability in the specific capture of low concentrations of phosphorylated peptides in complex practical biological specimens.

Figure 10. MALDI-TOF MS spectra: (a) direct analysis of non-fat milk digest, and (b) enriched by mag-MOF nanofibers; (c, e) direct analysis of human serum, and (d, f) enriched by mag-MOF nanofibers; the dephosphorylated peptides are labeled with # symbols.

Mag-MOF nanofiber-based membrane for phosphorylated peptide enrichment in a continuous filtering mode. ACS Paragon1112 Plus Environment

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Because of the HAP nanowires have high aspect ratios, the as-synthesized mag-MOF nanofibers can be further self-assembled into a membrane, and it could be used for the selective capture of phosphorylated peptides in a continuous filtering mode. As presented in Figure 11a, the magMOF nanofiber-based membrane with a diameter of 4 cm was prepared though a facile filtration procedure. The obtained membrane can be picked up using a tweezer (Figure 11b), be cut into a small-sized membrane and fixed in a filter container (Figure 11c) for the continuous enrichment procedure using the filtering equipment (Figure 11d).

Figure 11. Digital images: (a) a mag-MOF nanofiber-based membrane, (b) the obtained membrane can be picked up using a tweezer, (c) a filter container loaded with the mag-MOF nanofiber-based membrane, and (d) the continuous filtering enrichment equipment.

The enrichment performance of mag-MOF nanofiber-based membrane is studied. As displayed in Figure S5 (Supporting Information), three identified phosphorylated peptides were detected. Moreover, in comparison to mag-MOF nanofibers, the mag-MOF nanofiber-based membrane exhibited almost the same enrichment results, including the signal intensities of three identified phosphorylated peptides (Figure 12a), the detection limit (Figure 12b), the capture recovery



(Figure 12c), and the capture capacity (Figure 12d). These results proved that the mag-MOF nanofiber-based membrane has excellent enrichment ability in a continuous filtering enrichment mode. This study provides an alternative and effective approach for the capture of low concentrations of phosphorylated peptides in biological specimens.

Figure 12. The comparison of enrichment performance of mag-MOF nanofibers and mag-MOF nanofiber-based membrane: (a) the signal intensities of three identified phosphorylated peptides (β1, β2, β3) after enrichment from β-casein digest, (b) the detection limit and corresponding S/N ratio, (c) the capture recovery, and (d) the capture capacity.

CONCLUSION In this research, the magnetic metal-organic framework (mag-MOF) nanofibers with a porous structure, high specific surface area and pore volume, good hydrophilicity, and unique magnetic response property was successfully fabricated from a nanowire-directed ACS Paragon1112 Plus Environment

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templating process. The immobilization of magnetic nanoparticles and formation of MOF nanocrystals on the surface of inorganic nanowires could be convenient realized without extra surface modification of organic linkers. Moreover, in the capture and identification of low-abundant phosphorylated peptides from both standard protein digests and practical biological mixtures, the mag-MOF nanofibers were demonstrated to have a high selectivity, high detection sensitivity, desirable capture recovery, large capture capacity, good repeatability, and practicable application. Additionally, the mag-MOF nanofiberbased membrane was proposed for the continuous filtering enrichment approach. It is believed that the as-prepared mag-MOF nanofibers could be potential candidates for enriching phosphorylated peptides from biological specimens. What’s more, this research may provides new ideas for the preparation of functional MOF nanofibers with different immobilized metal ions for the selective extraction and identification of target biomolecules.

ASSOCIATED CONTENT Supporting Information It contains the following contents: detailed description of material characterization, capture recovery test, MALDI-TOF MS and nano LC-MS/MS analysis, database searching, nitrogen adsorption-desorption curves, pore-size distribution curves, digital images, SEM image, MS spectra, the comparison of specific surface area and pore volume between several magnetic MOF materials, characterization results and phosphorylated peptide capture performance of mag-MOF nanofibers with different MOF contents, detailed information of detected phosphorylated peptides from α-casein, β-casein, non-fat milk, human serum, and human saliva.

AUTHOR INFORMATION * Corresponding Author



E-mail: [email protected]; Tel: 0086-571-63732772; Fax: 0086-571-63732772. ORCID Mingyang Xing: 0000-0002-0518-2849 Jie Li: 0000-0003-4934-4245 NOTES The authors declare no competing financial interest.

ACKNOWLEDGEMENTS Financial support from the Zhejiang Public Welfare Technology Research Plan/Rural Agriculture (LGN18B010001) and Zhejiang Provincial Collaborative Innovation Center of Agricultural Biological Besources Biochemical Manufacturing (2016KF0005).

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For Table of Contents Use only

Magnetic metal-organic framework nanofibers were developed for the specific capture and identification of low abundant phosphorylated peptides for promising early diagnosis of diseases.


Facile Fabrication of Magnetic MetalâOrganic Framework Nanofibers

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