CN116790023A - 一种自组装富含钛的酰肼连接的多孔有机聚合物及其应用 - Google Patents
一种自组装富含钛的酰肼连接的多孔有机聚合物及其应用 Download PDFInfo
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Abstract
本发明涉及一种自组装富含钛的酰肼连接的多孔有机聚合物,通过使用水合肼、1,3,5‑苯三羧酸三甲酯(TP)和2,3‑二羟基对苯二甲醛(DHTA)作为构建模块,接着通过螯合作用固定金属阳离子Ti4+,合成了富含钛的肼连接的多孔有机聚合物(hydrazide‑POPs‑Ti4+)。对比传统的亲水材料,该材料的制备过程简单,节省了大量时间;可以同时富集糖肽和磷酸化肽并且通过优化反应时间,温度,原料浓度不断调整材料的微观形貌和尺寸,从而获取性能最佳的材料,大大提高了糖肽和磷酸化肽的富集能力。
Description
技术领域
本发明涉及材料制备及应用技术领域,具体涉及一种自组装富含钛的酰肼连接的多孔有机聚合物及其应用。
背景技术
翻译后修饰(PTMs)在扩展蛋白质组的复杂性方面发挥着重要作用。PTMs通过改变蛋白质的各种功能和活性,如细胞生长、增殖、分化、凋亡和细胞信号传导等来调节生物过程异常的糖肽和磷酸化肽被普遍应用于临床蛋白质组学研究和与疾病相关的生物标志物的发现。已经发现,一些人类疾病,如癌症和神经退行性疾病,与异常的糖基化和磷酸化密切相关。到目前为止,研究兴趣集中在细胞活动中的糖基化或磷酸化的个别功能。然而,这两种PTMs通常是相互作用的,并不单独作用于某个特定的生物过程。例如,据报道,阿尔茨海默病(AD)与tau蛋白糖基化和磷酸化的异常密切相关。因此,对这两种PTMs的综合分析对诊断疾病和发现潜在的生物标志物具有相当重要的意义。质谱法(MS)在PTMs的研究中起着至关重要的作用,因为它具有出色的灵敏度和高通量。然而,由于糖肽和磷酸化肽的电离效率低,以及非目标肽的干扰,复杂的生物样品必须在质谱分析前进行有效的预处理,这使得目标肽的直接质谱分析变得困难。因此,在质谱分析之前,对糖肽和磷酸化肽进行选择性富集和分离至关重要。
在以往的糖蛋白/糖肽富集策略中,依靠糖肽比非糖肽更高的亲水性,亲水相互作用液相色谱法(HILIC)得到了广泛应用。HILIC有着优异的MS兼容性、不破坏糖肽的结构和选择性分离等特性。此外,固定化金属亲和色谱法(IMAC)是富集磷酸肽的主要方法之一。在最常用的金属离子中,Ti4+在富集磷酸化肽方面有更好的表现,因为它对多/单体磷酸肽没有偏见,而且减少了非特异性结合。结合HILIC和IMAC策略制备的材料已经被开发出来,用于同时富集糖肽和磷酸肽,这大大促进了糖蛋白组学和磷酸蛋白组学的发展。然而,这些材料存在改性困难、合成过程中存在冗余、吸附能力弱等问题。
多孔有机聚合物(POPs)是一种被广泛研究的吸附材料。通过对有机配体的精心设计和调整,可以获得具有较高比表面积、优异的吸附性能和功能化的材料。此外,POPs的高聚合度和共价键使其性质牢固稳定,不溶于多种介质,这使其与其他类型的多孔材料有明显区别。然而,解决持久性有机聚合物的疏水性和引入特定的官能团仍然具有挑战性。
因此,开发一种富含钛的酰肼连接的亲水类多孔有机聚合物材料,来同时富集糖肽和磷酸化肽是一种新的需求。
发明内容
本发明的目的是克服现有技术存在的缺陷,提供一种富含钛的酰肼连接的多孔有机聚合物的制备方法及其在糖基化和磷酸化蛋白质组学的应用。
实现本发明目的的技术方案是提供一种自组装富含钛的酰肼连接的多孔有机聚合物,其制备方法包括如下步骤:
(1)取一定量的1,3,5-苯三羧酸三甲酯(TP)溶解于水合肼中配置成一定浓度的溶液;
(2)取出容量为25mL的聚四氟乙烯内衬的不锈钢反应釜,将步骤(1)所得的溶液倒入其中;
(3)将步骤(2)的反应釜放入烘箱中一定温度反应数小时;
(4)将步骤(3)所得的产物用去离子水和乙醇充分洗涤,除去产物表面的杂质与原料单体,并在真空干燥器中干燥,得到酰肼连接的材料;
(5)将步骤(4)中所得产物分散到均三甲苯/1,4-二氧六环混合溶液中,将2,3-二羟基对苯二甲醛(DHTA)分散到乙酸和均三甲苯/1,4-二氧六环溶剂三者混合物中,再将两个溶液混合到一起后室温搅拌2.5小时,用四氢呋喃和丙酮洗涤数次,得到表面富含磷酸基团的有机聚合物材料;
(6)将步骤(5)中所得产物分散到的Ti(SO4)2溶液中,室温震荡2小时;
(7)将步骤(6)所得的产物用去离子水和乙醇充分洗涤,并在真空干燥器中干燥,即得所述多孔有机聚合物材料。
进一步的,步骤(1)中所述1,3,5-苯三羧酸三甲酯(TP)浓度为31.892mg/mL;1,3,5-苯三羧酸三甲酯(TP)和水合肼的摩尔比为1:3。
进一步的,步骤(3)中所述的反应温度为100℃,反应时间12小时。
进一步的,步骤(5)中所述均三甲苯/1,4-二氧六环的体积比为v/v=1/1。
进一步的,步骤(5)中所述产物在均三甲苯/1,4-二氧六环和乙酸三者混合溶液中的浓度为4.17mg/mL,所述DHTA在均三甲苯/1,4-二氧六环和乙酸三者混合溶液中的浓度为3.1125mg/mL。
进一步的,步骤(6)中所述Ti(SO4)2溶液浓度为25mmol/L。
一种自组装富含钛的酰肼连接的多孔有机聚合物在糖肽选择性富集的应用,糖肽质谱检测包括以下步骤:将500μg多孔有机聚合物材料分散到100μL含有糖肽、3%体积比三氟乙酸(TFA)和90%体积比乙腈(ACN)的离心管中,37℃富集1h;之后用3%体积比TFA和90%体积比ACN的缓冲液充分洗涤三次;然后用10μL的0.1%体积比TFA和30%体积比ACN洗脱30min,取1μL洗脱液点靶,用2,5-二羟基苯甲酸(DHB)作为基质,进行基质辅助激光解吸电离飞行时间质谱(MALDI-TOFMS)或纳升液相色谱-质谱联用(NanoLC-MS/MS)检测。
一种自组装富含钛的酰肼连接的多孔有机聚合物在磷酸化肽段选择性富集的应用,磷酸化肽质谱检测包括以下步骤:将500μg多孔有机聚合物材料分散到100μL含有磷酸化肽、0.5%体积比TFA和50%体积比ACN的离心管中,37℃富集45min,之后用0.5%体积比TFA和50%体积比ACN的缓冲液充分洗涤三次;然后用10μL的0.4M氨水洗脱30min,取1μL洗脱液点靶,用2,5-二羟基苯甲酸(DHB)作为基质,进行MALDI-TOFMS或NanoLC-MS/MS检测。
采用上述技术方案后,本发明具有以下积极的效果:
(1)本发明通过使用水合肼、1,3,5-苯三羧酸三甲酯(TP)和2,3-二羟基对苯二甲醛(DHTA)作为构建模块,接着通过螯合作用固定金属阳离子Ti4+,合成了富含钛的肼连接的多孔有机聚合物(hydrazide-POPs-Ti4+),制备过程简单,节省了大量时间。
(2)本发明可以同时富集糖肽和磷酸化肽并且通过优化反应时间,温度,原料浓度不断调整材料的微观形貌和尺寸,从而获取性能最佳的材料,大大提高了糖肽和磷酸化肽的富集能力。
附图说明
为了使本发明的内容更容易被清楚地理解,下面根据具体实施例并结合附图,对本发明作进一步详细的说明,其中
图1为本发明富含钛的酰肼连接的多孔有机聚合物材料的扫描电子显微镜照片;
图2为本发明富含钛的酰肼连接的多孔有机聚合物材料的元素分布图;
图3为本发明富含钛的酰肼连接的多孔有机聚合物材料的红外光谱图;
图4为本发明富含钛的酰肼连接的多孔有机聚合物材料富集HRP中的糖肽的质谱图(★代表糖肽);
图5为本发明富含钛的酰肼连接的多孔有机聚合物材料富集β-casein中的磷酸化肽的质谱图(●代表磷酸化肽);
图6为本发明富含钛的酰肼连接的多孔有机聚合物材料富集糖肽段检测限(0.1fmol/μL)的质谱图(★代表糖肽);
图7为本发明富含钛的酰肼连接的多孔有机聚合物材料富集磷酸化肽段检测限(0.5fmol)的质谱图(●代表磷酸化肽);
图8为本发明富含钛的酰肼连接的多孔有机聚合物材料富集混合蛋白(BSA:HRP=2000:1)中的糖肽的质谱图(★代表糖肽);
图9为本发明富含钛的酰肼连接的多孔有机聚合物材料富集混合蛋白(BSA:β-casein=1000:1)中的磷酸化肽的质谱图(●代表磷酸化肽);
图10为本发明富含钛的酰肼连接的多孔有机聚合物材料富集人血清中糖肽段的维恩图;
图11为本发明富含钛的酰肼连接的多孔有机聚合物材料富集人血清中磷酸化肽段的维恩图;
具体实施方式
实施例1富含钛的酰肼连接的多孔有机聚合物材料的合成
包括如下步骤:
(1)将318.92mg的1,3,5-苯三羧酸三甲酯(TP)溶解于10mL的水合肼中配置成31.892mg/mL浓度的溶液;
(2)取出容量为25mL的聚四氟乙烯内衬的不锈钢反应釜,将步骤(1)所得的溶液倒入其中;
(3)将步骤(2)的反应釜放入烘箱中100℃反应12h;
(4)将步骤(3)所得的产物用去离子水和乙醇充分洗涤,除去产物表面的杂质与原料单体,并在真空干燥器中干燥,得到酰肼连接的材料;
(5)将步骤(4)中所得产物分散到均三甲苯/1,4-二氧六环混合溶液中,将2,3-二羟基对苯二甲醛(DHTA)分散到乙酸和均三甲苯/1,4-二氧六环溶剂三者混合物中,再将两个溶液混合到一起后室温搅拌2.5小时,和均三甲苯/1,4-二氧六环(v/v=1/1)溶剂混合物中,室温搅拌2.5h,用四氢呋喃和丙酮洗涤数次,得到表面富含磷酸基团的多孔有机聚合物材料,所述均三甲苯/1,4-二氧六环的体积比为v/v=1/1,所述产物在均三甲苯/1,4-二氧六环和乙酸三者混合溶液中的浓度为4.17mg/mL,所述DHTA在均三甲苯/1,4-二氧六环和乙酸三者混合溶液中的浓度为3.1125mg/mL;
(6)将步骤(5)中所得产物分散到25mmol/L的Ti(SO4)2溶液中,室温震荡2h;
(7)将步骤(6)所得的产物用去离子水和乙醇充分洗涤,并在真空干燥器中干燥,即得所述多孔有机聚合物材料。
所得的富含钛的酰肼连接的多孔有机聚合物材料的扫描电子显微镜照片(20KV,飞利浦XL30电子显微镜,荷兰)如图1所示,元素分布图如图2所示,傅里叶红外变换光谱图(赛默飞NIcoletiS10,美国)如图3所示,可以观察到此材料是均匀的球体,平均直径约为200nm。EDX显示了C、N、O和Ti元素的存在。傅里叶红外变换光谱图表明了官能团的成功接枝。
实施例2富含钛的酰肼连接的多孔有机聚合物材料在富集HRP中的糖肽的应用
包括如下步骤:
(1)试样的准备:辣根过氧化物酶(HRP)在25mmol/LNH4HCO3溶液中37℃酶解16h;
(2)富集:0.5mg多孔有机聚合物材料分散到200μL的3%体积比的三氟乙酸(TFA)、7%体积比的去离子水和90%体积比的乙腈(ACN)的离心管中,再加入2μL步骤(1)制备的样品,在37℃富集1h;用3%体积比的TFA、7%体积比的去离子水和90%体积比的ACN的缓冲液充分洗涤并离心分离3次;加入10μL69.9%体积比的ACN和30%体积比的去离子水的洗脱液,37℃洗脱30min,离心分离获取上清液;
(3)质谱分析:取1μL步骤(2)所得的上清液点靶,进行质谱分析,质谱图如图4所示,对于糖肽的富集,在用hydrazide-POPs-Ti4+富集后检测到18种糖肽。图6是富含钛的酰肼连接的多孔有机聚合物材料HRP中的糖肽检测限(0.1fmol/μL),说明当HRP浓度为1fmol/ul时,此材料依然可以捕获到糖肽,具有很高的灵敏度。
实施例3富含钛的酰肼连接的多孔有机聚合物材料在富集β-酪蛋白中的磷酸化肽的应用
(1)试样的准备:β-casein(β-酪蛋白)在25mmol/LNH4HCO3溶液中37℃酶解16h;
(2)富集:0.5mg纳米材料分散到100μL的0.1%体积比TFA50%体积比ACN离心管中,再加入1μL步骤(1)制备的样品,在37℃富集30min;用0.1%体积比TFA和50%体积比ACN的缓冲液洗涤并离心分离3次;10μL0.4M氨水洗脱10min,离心分离获取上清液。
(3)质谱分析:取1μL步骤(2)所得的上清液点靶,进行质谱分析,质谱图如图5所示,用hydrazide-POPs-Ti4+富集后,检测到9个背景清晰的磷酸化肽。图7是富含钛的酰肼连接的多孔有机聚合物材料富集β-casein中的磷酸化肽检测限(0.5fmol),说明当β-casein浓度为0.5fmol时,此材料依然可以捕获到磷酸化肽,具有很高的灵敏度。
实施例4富含钛的酰肼连接的多孔有机聚合物材料在富集混合蛋白中的糖肽的应用
包括以下步骤:
(1)试样准备:牛血清白蛋白(BSA)先用二硫苏糖醇和碘乙酰胺还原烷基化,然后在37℃酶解16h;辣根过氧化物酶(HRP)在25mMNH4HCO3溶液中37℃酶解16h。将牛血清白蛋白(BSA)和辣根过氧化物酶(HRP)酶解物以2000:1摩尔比加到含有3%体积比的TFA、7%体积比的去离子水和90%体积比的ACN的离心管中;
(2)富集:0.5mg实施例1所得的材料分散到200μL含有步骤(1)的糖肽的3%体积比的TFA、7%体积比的去离子水和90%体积比的ACN的离心管中,37℃富集1h;用3%体积比的TFA、7%体积比的去离子水和90%体积比的ACN缓冲液充分洗涤并离心分离3次;加入10μL69.9%体积比的ACN和30%体积比的去离子水的洗脱液,37℃洗脱30min,离心分离获取上清液;
(3)质谱分析:取1μL步骤(2)所得的洗脱液点靶,进行质谱分析,图8是富含钛的酰肼连接的多孔有机聚合物材料富集混合蛋白(BSA:HRP=2000:1)中的糖肽的质谱图,当BSA:HRP=2000:1时,在用hydrazide-POPs-Ti4+富集后,谱图中仍然可以检测到3个糖肽。
实施例5富含钛的酰肼连接的多孔有机聚合物材料在富集混合蛋白中的磷酸化肽的应用
包括以下步骤:
(1)试样的准备:牛血清白蛋白(BSA)先用二硫苏糖醇和碘乙酰胺还原烷基化,然后在37℃酶解16h;β-casein在25mMNH4HCO3溶液中37℃酶解16h。将牛血清白蛋白(BSA)和β-casein以1000:1摩尔比加到0.5%体积比的TFA、49.5%体积比的去离子水和50%体积比的ACN的离心管中;
(2)富集:0.5mg实施例1所得的聚合物材料分散到100μL含有步骤(1)的磷酸化肽的0.5%体积比的TFA、50%体积比的ACN的离心管中,37℃富集45min;用0.5%体积比TFA和50%体积比ACN的缓冲液洗涤并离心分离3次;10μL0.4M氨水洗脱30min。
(3)质谱分析:取1μL步骤(2)所得的洗脱液点靶,进行质谱分析,多孔有机聚合物材料富集混合蛋白(非磷酸蛋白BSA:磷酸化蛋白β-casein=1000:1)中的磷酸化肽的质谱图如图9所示,用hydrazide-POPs-Ti4+富集后,从摩尔比为1:1000的β-casein和BSA消化物的混合物中仍能检测到观察到4个磷酸肽的峰。
实施例6富含钛的酰肼连接的多孔有机聚合物材料在富集人血清中的糖肽的应用
包括以下步骤:
(1)试样的准备:获得的人血清先用二硫苏糖醇和碘乙酰胺还原烷基化,然后在37℃酶解16h;
(2)富集:0.5mg多孔有机聚合物分散到100μL含有步骤(1)的糖肽的3%体积比的三氟乙酸、7%体积比的去离子水和90%体积比的乙腈的离心管中,37℃富集1h;用3%体积比的三氟乙酸、7%体积比的去离子水和90%体积比的乙腈缓冲液充分洗涤并离心分离5次;加入10μL0.1%体积比的三氟乙酸,30%体积比的乙腈和69.9%体积比的去离子水的洗脱液,37℃孵育30min,洗脱两次,离心分离获取上清液;
(3)质谱分析:收集步骤(2)所得的洗脱液,在37℃下去糖基化16h,脱盐冻干并进行Nano-LC-MS/MS检测,所得数据的维恩图如图10所示,在正常对照组的血清中,共捕获了对应于129种糖蛋白的201种糖肽和153个糖基化位点,同时,在乳腺癌患者的内源性血清中捕获了186个糖肽和124个糖基化位点,对应于117个糖蛋白。
实施例7富含钛的酰肼连接的多孔有机聚合物材料在富集人血清中的磷酸化肽的应用
包括以下步骤:
(1)试样的准备:获得的人血清先用二硫苏糖醇和碘乙酰胺还原烷基化,然后在37℃酶解16h;
(2)富集:0.5mg多孔有机聚合物分散到100μL含有步骤(1)的磷酸化肽的0.5%体积比的三氟乙酸、49.9%体积比的去离子水和50%体积比的乙腈的离心管中,37℃富集45min;用0.5%体积比的三氟乙酸、49.9%体积比的去离子水和50%体积比的乙腈缓冲液充分洗涤并离心分离5次;加入10μL0.4M氨水洗脱液,37℃孵育30min,洗脱两次,离心分离获取上清液;
(3)质谱分析:收集步骤(2)所得的洗脱液,脱盐冻干并进行Nano-LC-MS/MS检测,所得数据的维恩图如图11所示,在正常对照组的血清中,共捕获了属于21种磷蛋白的26种磷酸肽和26个磷酸化位点,同时,在乳腺癌患者的内源性血清中捕获了60个磷酸肽和54个磷酸化位点,属于50个磷蛋白。
以上所述的具体实施例,对本发明的目的、技术方案和有益效果进行了进一步详细说明,所应理解的是,以上所述仅为本发明的具体实施例而已,并不用于限制本发明,凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (8)
1.一种自组装富含钛的酰肼连接的多孔有机聚合物,其特征在于,其制备方法包括如下步骤:
(1)取一定量的1,3,5-苯三羧酸三甲酯(TP)溶解于水合肼中配置成一定浓度的溶液;
(2)取出容量为25mL的聚四氟乙烯内衬的不锈钢反应釜,将步骤(1)所得的溶液倒入其中;
(3)将步骤(2)的反应釜放入烘箱中一定温度反应数小时;
(4)将步骤(3)所得的产物用去离子水和乙醇充分洗涤,除去产物表面的杂质与原料单体,并在真空干燥器中干燥,得到酰肼连接的材料;
(5)将步骤(4)中所得产物分散到均三甲苯/1,4-二氧六环混合溶液中,将2,3-二羟基对苯二甲醛(DHTA)分散到乙酸和均三甲苯/1,4-二氧六环溶剂三者混合物中,再将两个溶液混合到一起后室温搅拌2.5小时,用四氢呋喃和丙酮洗涤数次,得到表面富含磷酸基团的有机聚合物材料;
(6)将步骤(5)中所得产物分散到的Ti(SO4)2溶液中,室温震荡2小时;
(7)将步骤(6)所得的产物用去离子水和乙醇充分洗涤,并在真空干燥器中干燥,即得所述多孔有机聚合物材料。
2.根据权利要求1所述的自组装富含钛的酰肼连接的多孔有机聚合物,其特征在于,步骤(1)中所述1,3,5-苯三羧酸三甲酯(TP)浓度为31.892mg/mL;1,3,5-苯三羧酸三甲酯(TP)和水合肼的摩尔比为1:3。
3.根据权利要求1所述的自组装富含钛的酰肼连接的多孔有机聚合物,其特征在于,步骤(3)中所述的反应温度为100℃,反应时间12小时。
4.根据权利要求1所述的自组装富含钛的酰肼连接的多孔有机聚合物,其特征在于,步骤(5)中所述均三甲苯/1,4-二氧六环的体积比为v/v=1/1。
5.根据权利要求1所述的自组装富含钛的酰肼连接的多孔有机聚合物,其特征在于,步骤(5)中所述产物在均三甲苯/1,4-二氧六环和乙酸三者混合溶液中的浓度为4.17mg/mL,所述DHTA在均三甲苯/1,4-二氧六环和乙酸三者混合溶液中的浓度为3.1125mg/mL。
6.根据权利要求1所述的自组装富含钛的酰肼连接的多孔有机聚合物,其特征在于:步骤(6)中所述Ti(SO4)2溶液浓度为25mmol/L。
7.一种如权利要求1所述的自组装富含钛的酰肼连接的多孔有机聚合物在糖肽选择性富集的应用,其特征在于,糖肽质谱检测包括以下步骤:将500μg多孔有机聚合物材料分散到100μL含有糖肽、3%体积比三氟乙酸(TFA)和90%体积比乙腈(ACN)的离心管中,37℃富集1h;之后用3%体积比TFA和90%体积比ACN的缓冲液充分洗涤三次;然后用10μL的0.1%体积比TFA和30%体积比ACN洗脱30min,取1μL洗脱液点靶,用2,5-二羟基苯甲酸(DHB)作为基质,进行基质辅助激光解吸电离飞行时间质谱(MALDI-TOFMS)或纳升液相色谱-质谱联用(NanoLC-MS/MS)检测。
8.一种如权利要求1所述的自组装富含钛的酰肼连接的多孔有机聚合物在磷酸化肽段选择性富集的应用,其特征在于,磷酸化肽质谱检测包括以下步骤:将500μg多孔有机聚合物材料分散到100μL含有磷酸化肽、0.5%体积比TFA和50%体积比ACN的离心管中,37℃富集45min,之后用0.5%体积比TFA和50%体积比ACN的缓冲液充分洗涤三次;然后用10μL的0.4M氨水洗脱30min,取1μL洗脱液点靶,用2,5-二羟基苯甲酸(DHB)作为基质,进行MALDI-TOFMS或NanoLC-MS/MS检测。
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