一针重复2万亿段代码,我「逆向工程」了辉瑞疫苗!
共 48419字,需浏览 97分钟
· 2020-12-30
新智元报道
新智元报道
来源:reddit
编辑:小匀
【新智元导读】从辉瑞疫苗被批准以后,它就被置于世界的聚光灯下。近日,一位程序员从计算机科学的角度,对辉瑞疫苗的设计进行了「逆向工程」,文章引起不小的反响,从信头 (Header)、元数据(Metadata),到帮助伪装躲过人体免疫系统防火墙的 Ψ 分子,一支疫苗有2万亿段重复的代码,我们看到了计算机与生物学那颇为神秘的联系。
辉瑞疫苗,逆向工程?
UUC)的修改都是同义的。疫苗的RNA编码不同,但会产生相同的氨基酸和蛋白质。"],[20,"\n","24:\"bUQk\""],[20,"\n","24:\"PTbn\""],[20,"如果我们仔细观察,我们会发现大部分的变化发生在密码子的第三个位置,上面有一个' 3 '。如果我们检查通用密码子表,我们会发现第三个位置通常与产生的氨基酸无关。"],[20,"\n","24:\"P6ah\""],[20,"\n","24:\"RKPu\""],[20,"所以,这些变化是同义的,但为什么会有这些变化呢?仔细观察,我们发现除了一个变化之外,所有的变化都会导致更多的C和G。"],[20,"\n","24:\"ZGRy\""],[20,"\n","24:\"ujmR\""],[20,"你为什么要这么做?如上所述,我们的免疫系统会对「外源性」RNA进行攻击,为了逃避检测,RNA中的「U」已经被ψ所取代了。"],[20,"\n","24:\"GYJ0\""],[20,"\n","24:\"i3b4\""],[20,"然而,事实证明,含有更多G和C的RNA也能更有效地转化为蛋白质,这已经在疫苗RNA中实现了只要有可能就用G和C替换许多字符。"],[20,"\n","24:\"xdD4\""],[20,"\n","24:\"aXIu\""],[20,"真正的刺突蛋白"],[20,"\n","24:\"OY8r\"|heading:\"title\""],[20,"\n","24:\"4jkI\""],[20,"疫苗RNA的下3777个字符类似于「密码子优化」,可以添加大量的C和G。"],[20,"\n","24:\"GP55\""],[20,"\n","24:\"mHHt\""],[20,{"gallery":"https://uploader.shimo.im/f/0bmEXwKd2EC33j3P.png!thumbnail"},"29:0|30:0|3:\"711\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"215\"|ori-width:\"711\""],[20,"\n","24:\"O7u7\""],[20,"\n","24:\"S6RY\""],[20,"这里我们看到同义的RNA变化。例如,在第一个密码子中CUU变成了CUG。这给疫苗增加了另一个「G」,我们知道这有助于提高蛋白质的生产。"],[20,"\n","24:\"kr4D\""],[20,"\n","24:\"qTAQ\""],[20,"当我们比较疫苗中的整个刺突蛋白时,所有的变化都是同义的。除了两个,这就是我们在这里看到的。"],[20,"\n","24:\"pnwO\""],[20,"\n","24:\"zGzF\""],[20,"上面的第三和第四个密码子代表了实际的变化。那里的K和V氨基酸都被P或脯氨酸所取代。对于「K」,这需要改变三次(「!!」),而对于「V」,这只需要改变两次(「!!」)。"],[20,"\n","24:\"Er2t\""],[20,"\n","24:\"lyjz\""],[20,"事实证明,这两个变化极大地提高了疫苗的效率。"],[20,"\n","24:\"kQPI\""],[20,"\n","24:\"o7BU\""],[20,"那么这里发生了什么?如果你看一个真正的冠状病毒粒子,你可以看到刺突蛋白:"],[20,"\n","24:\"3dSX\""],[20,"\n","24:\"4uyq\""],[20,{"gallery":"https://uploader.shimo.im/f/IS2OUFuSOlUJUMTw.png!thumbnail"},"29:0|30:0|3:\"943\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"672\"|ori-width:\"943\""],[20,"\n","24:\"hAu7\""],[20,"\n","24:\"QFV3\""],[20,"这些刺钉被安装在病毒体内(「核衣壳蛋白」)。但问题是,我们的疫苗只会产生刺突,我们不会把它们植入任何一种病毒体内。"],[20,"\n","24:\"sebh\""],[20,"\n","24:\"wC3y\""],[20,"结果是,未经修饰的,独立的刺突蛋白崩溃成不同的结构。如果作为疫苗注射,这确实会使我们的身体产生免疫力。但只针对崩溃的刺突蛋白。"],[20,"\n","24:\"Qba0\""],[20,"\n","24:\"m4p7\""],[20,"真正的冠状病毒是带着尖刺的。在这种情况下,疫苗不会很有效。"],[20,"\n","24:\"f2FP\""],[20,"\n","24:\"8JB8\""],[20,"那么该怎么办呢?"],[20,"\n","24:\"ICR5\""],[20,"\n","24:\"3H1H\""],[20,"2017年,有人描述了如何在正确的位置放置一个双脯氨酸替代,将使SARS-CoV-1和MERS S蛋白形成「预融合」结构,即使不是整个病毒的一部分。这是因为脯氨酸是一种非常坚硬的氨基酸。它就像一种夹板,在我们需要向免疫系统展示的状态下稳定蛋白质。"],[20,"\n","24:\"W3tM\""],[20,"\n","24:\"VnUj\""],[20,"蛋白质的末端,下一步"],[20,"\n","24:\"FAtJ\"|heading:\"title\""],[20,"\n","24:\"sTqb\""],[20,"如果我们浏览其余的源代码,我们会在刺突蛋白的末端遇到一些小的修改:"],[20,"\n","24:\"YbvU\""],[20,"\n","24:\"NRTt\""],[20,{"gallery":"https://uploader.shimo.im/f/hROE13Gv1eIb3OzF.png!thumbnail"},"29:0|30:0|3:\"727\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"197\"|ori-width:\"727\""],[20,"\n","24:\"oDYT\""],[20,"在蛋白质的末端,我们会发现一个「停止」密码子,在这里用小写的「s」表示。这是一种礼貌的说法,表示蛋白质应该到此为止。最初的病毒使用UAA终止密码子,疫苗使用两个UGA终止密码子,也许只是为了更好的措施。"],[20,"\n","24:\"OYg5\""],[20,"\n","24:\"oBiH\""],[20,"3 'UTR"],[20,"\n","24:\"Y1GI\"|heading:\"title\""],[20,"\n","24:\"TEnu\""],[20,"就像核糖体在5 '端需要引入,我们发现了' 5UTR,在蛋白质的末端我们发现了一个类似的结构,称为3 ' UTR。"],[20,"\n","24:\"kOrG\""],[20,"\n","24:\"0fad\""],[20,"关于3 ' UTR有很多说法,但这里引用维基百科的说法:「3 ' UTR在基因表达中起着至关重要的作用,它影响mRNA的定位、稳定性、输出和翻译效率。尽管我们目前对3 ' -UTRs有了解,但它们仍然是相对神秘的。」"],[20,"\n","24:\"Wlpy\""],[20,"\n","24:\"28nk\""],[20,"我们所知道的是,某些3 ' UTR在促进蛋白质表达方面非常成功。根据世卫组织的文件,辉瑞疫苗3 ' UTR是从「split (AES) mRNA的氨基末端增强子和编码12S核糖体RNA的线粒体中提取的,以保证RNA的稳定性和高总蛋白表达」。"],[20,"\n","24:\"4WmY\""],[20,"\n","24:\"or6H\""],[20,{"gallery":"https://uploader.shimo.im/f/7NO6x6dFyvuglDih.png!thumbnail"},"29:0|30:0|3:\"302\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"327\"|ori-width:\"302\""],[20,"\n","24:\"EbDX\""],[20,"\n","24:\"eYEy\""],[20,"The AAAAAAAAAAAAAAAAAAAAAA end of it all"],[20,"\n","24:\"noiV\"|heading:\"title\""],[20,"\n","24:\"Pj2q\""],[20,"mRNA的最末端是聚腺苷化的。这是一种以「AAAAAAAAAAAAAAAAAAAAAA」的奇特结尾。"],[20,"\n","24:\"0bqn\""],[20,"\n","24:\"71Pu\""],[20,"似乎,就连mRNA似乎也受够了这个糟糕的2020年!"],[20,"\n","24:\"IlGa\""],[20,"\n","24:\"7SFz\""],[20,"mRNA可以重复使用很多次,但在这个过程中,它也会在末端失去一些A。一旦A耗尽,mRNA就不再起作用而被丢弃。这样,「多聚腺苷酸尾(Poly-A Tail)」就可以防止其退化。"],[20,"\n","24:\"1JVA\""],[20,"\n","24:\"qXT2\""],[20,"有研究表明,对于mRNA疫苗来说,A的最佳数量是多少。我在公开文献中读到,这个数字在120左右达到了顶峰。"],[20,"\n","24:\"F6Os\""],[20,"\n","24:\"Z67Q\""],[20,"BNT162b2疫苗的是:"],[20,"\n","24:\"ihrg\""],[20,"\n","24:\"7YX2\""],[20,{"gallery":"https://uploader.shimo.im/f/tusFvw4FJ0tIpcku.png!thumbnail"},"29:0|30:0|3:\"724\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"149\"|ori-width:\"724\""],[20,"\n","24:\"7QyT\""],[20,"\n","24:\"N36z\""],[20,"这是30个A,然后是「10个核苷酸连接体」(GCAUAUGACU),再后面是70个A。"],[20,"\n","24:\"69k4\""],[20,"\n","24:\"SqK1\""],[20,"总结"],[20,"\n","24:\"vwUI\"|heading:\"title\""],[20,"如果上面的一切让你感到云里雾里,作者在这里为您准备了一份「太长不看版」:"],[20,"\n","24:\"OQLJ\""],[20,"\n","24:\"tBD5\""],[20,"帽子来确保RNA看起来像普通的mRNA"],[20,"\n","24:\"iWYP\""],[20,"\n","24:\"P0FT\""],[20,"已知的成功和优化的5 ' UTR"],[20,"\n","24:\"2Ww5\""],[20,"\n","24:\"s1r6\""],[20,"密码子优化信号肽,将刺突蛋白送到正确的位置(100%从原始病毒复制)"],[20,"\n","24:\"pKRX\""],[20,"\n","24:\"ozvP\""],[20,"原始刺的密码子优化版本,有两个「脯氨酸」替代,以确保蛋白质以正确的形式出现"],[20,"\n","24:\"6box\""],[20,"\n","24:\"ccP0\""],[20,"一个已知的成功和优化的3 ' UTR"],[20,"\n","24:\"quj6\""],[20,"\n","24:\"6bWa\""],[20,"一个有点神秘的多聚腺苷酸尾(Poly-A Tail),里面有一个无法解释的「连接器」"],[20,"\n","24:\"GOHG\""],[20,"\n","24:\"AnWo\""],[20,"密码子优化在mRNA上增加了大量的G和C。与此同时,用ψ(1-甲基-3 ' -伪尿酰ψ)而不是U来帮助逃避我们的免疫系统,因此mRNA会停留足够长的时间,所以我们实际上可以帮助训练免疫系统。"],[20,"\n","24:\"h7hJ\""],[20,"\n","24:\"TTuP\""],[20,"\n","24:\"9BwE\""],[20,"\n","24:\"veIF\"|heading:\"title\""]]" style="letter-spacing: 0.544px; font-size: 15px;">
UUC)的修改都是同义的。疫苗的RNA编码不同,但会产生相同的氨基酸和蛋白质。"],[20,"\n","24:\"bUQk\""],[20,"\n","24:\"PTbn\""],[20,"如果我们仔细观察,我们会发现大部分的变化发生在密码子的第三个位置,上面有一个' 3 '。如果我们检查通用密码子表,我们会发现第三个位置通常与产生的氨基酸无关。"],[20,"\n","24:\"P6ah\""],[20,"\n","24:\"RKPu\""],[20,"所以,这些变化是同义的,但为什么会有这些变化呢?仔细观察,我们发现除了一个变化之外,所有的变化都会导致更多的C和G。"],[20,"\n","24:\"ZGRy\""],[20,"\n","24:\"ujmR\""],[20,"你为什么要这么做?如上所述,我们的免疫系统会对「外源性」RNA进行攻击,为了逃避检测,RNA中的「U」已经被ψ所取代了。"],[20,"\n","24:\"GYJ0\""],[20,"\n","24:\"i3b4\""],[20,"然而,事实证明,含有更多G和C的RNA也能更有效地转化为蛋白质,这已经在疫苗RNA中实现了只要有可能就用G和C替换许多字符。"],[20,"\n","24:\"xdD4\""],[20,"\n","24:\"aXIu\""],[20,"真正的刺突蛋白"],[20,"\n","24:\"OY8r\"|heading:\"title\""],[20,"\n","24:\"4jkI\""],[20,"疫苗RNA的下3777个字符类似于「密码子优化」,可以添加大量的C和G。"],[20,"\n","24:\"GP55\""],[20,"\n","24:\"mHHt\""],[20,{"gallery":"https://uploader.shimo.im/f/0bmEXwKd2EC33j3P.png!thumbnail"},"29:0|30:0|3:\"711\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"215\"|ori-width:\"711\""],[20,"\n","24:\"O7u7\""],[20,"\n","24:\"S6RY\""],[20,"这里我们看到同义的RNA变化。例如,在第一个密码子中CUU变成了CUG。这给疫苗增加了另一个「G」,我们知道这有助于提高蛋白质的生产。"],[20,"\n","24:\"kr4D\""],[20,"\n","24:\"qTAQ\""],[20,"当我们比较疫苗中的整个刺突蛋白时,所有的变化都是同义的。除了两个,这就是我们在这里看到的。"],[20,"\n","24:\"pnwO\""],[20,"\n","24:\"zGzF\""],[20,"上面的第三和第四个密码子代表了实际的变化。那里的K和V氨基酸都被P或脯氨酸所取代。对于「K」,这需要改变三次(「!!」),而对于「V」,这只需要改变两次(「!!」)。"],[20,"\n","24:\"Er2t\""],[20,"\n","24:\"lyjz\""],[20,"事实证明,这两个变化极大地提高了疫苗的效率。"],[20,"\n","24:\"kQPI\""],[20,"\n","24:\"o7BU\""],[20,"那么这里发生了什么?如果你看一个真正的冠状病毒粒子,你可以看到刺突蛋白:"],[20,"\n","24:\"3dSX\""],[20,"\n","24:\"4uyq\""],[20,{"gallery":"https://uploader.shimo.im/f/IS2OUFuSOlUJUMTw.png!thumbnail"},"29:0|30:0|3:\"943\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"672\"|ori-width:\"943\""],[20,"\n","24:\"hAu7\""],[20,"\n","24:\"QFV3\""],[20,"这些刺钉被安装在病毒体内(「核衣壳蛋白」)。但问题是,我们的疫苗只会产生刺突,我们不会把它们植入任何一种病毒体内。"],[20,"\n","24:\"sebh\""],[20,"\n","24:\"wC3y\""],[20,"结果是,未经修饰的,独立的刺突蛋白崩溃成不同的结构。如果作为疫苗注射,这确实会使我们的身体产生免疫力。但只针对崩溃的刺突蛋白。"],[20,"\n","24:\"Qba0\""],[20,"\n","24:\"m4p7\""],[20,"真正的冠状病毒是带着尖刺的。在这种情况下,疫苗不会很有效。"],[20,"\n","24:\"f2FP\""],[20,"\n","24:\"8JB8\""],[20,"那么该怎么办呢?"],[20,"\n","24:\"ICR5\""],[20,"\n","24:\"3H1H\""],[20,"2017年,有人描述了如何在正确的位置放置一个双脯氨酸替代,将使SARS-CoV-1和MERS S蛋白形成「预融合」结构,即使不是整个病毒的一部分。这是因为脯氨酸是一种非常坚硬的氨基酸。它就像一种夹板,在我们需要向免疫系统展示的状态下稳定蛋白质。"],[20,"\n","24:\"W3tM\""],[20,"\n","24:\"VnUj\""],[20,"蛋白质的末端,下一步"],[20,"\n","24:\"FAtJ\"|heading:\"title\""],[20,"\n","24:\"sTqb\""],[20,"如果我们浏览其余的源代码,我们会在刺突蛋白的末端遇到一些小的修改:"],[20,"\n","24:\"YbvU\""],[20,"\n","24:\"NRTt\""],[20,{"gallery":"https://uploader.shimo.im/f/hROE13Gv1eIb3OzF.png!thumbnail"},"29:0|30:0|3:\"727\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"197\"|ori-width:\"727\""],[20,"\n","24:\"oDYT\""],[20,"在蛋白质的末端,我们会发现一个「停止」密码子,在这里用小写的「s」表示。这是一种礼貌的说法,表示蛋白质应该到此为止。最初的病毒使用UAA终止密码子,疫苗使用两个UGA终止密码子,也许只是为了更好的措施。"],[20,"\n","24:\"OYg5\""],[20,"\n","24:\"oBiH\""],[20,"3 'UTR"],[20,"\n","24:\"Y1GI\"|heading:\"title\""],[20,"\n","24:\"TEnu\""],[20,"就像核糖体在5 '端需要引入,我们发现了' 5UTR,在蛋白质的末端我们发现了一个类似的结构,称为3 ' UTR。"],[20,"\n","24:\"kOrG\""],[20,"\n","24:\"0fad\""],[20,"关于3 ' UTR有很多说法,但这里引用维基百科的说法:「3 ' UTR在基因表达中起着至关重要的作用,它影响mRNA的定位、稳定性、输出和翻译效率。尽管我们目前对3 ' -UTRs有了解,但它们仍然是相对神秘的。」"],[20,"\n","24:\"Wlpy\""],[20,"\n","24:\"28nk\""],[20,"我们所知道的是,某些3 ' UTR在促进蛋白质表达方面非常成功。根据世卫组织的文件,辉瑞疫苗3 ' UTR是从「split (AES) mRNA的氨基末端增强子和编码12S核糖体RNA的线粒体中提取的,以保证RNA的稳定性和高总蛋白表达」。"],[20,"\n","24:\"4WmY\""],[20,"\n","24:\"or6H\""],[20,{"gallery":"https://uploader.shimo.im/f/7NO6x6dFyvuglDih.png!thumbnail"},"29:0|30:0|3:\"302\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"327\"|ori-width:\"302\""],[20,"\n","24:\"EbDX\""],[20,"\n","24:\"eYEy\""],[20,"The AAAAAAAAAAAAAAAAAAAAAA end of it all"],[20,"\n","24:\"noiV\"|heading:\"title\""],[20,"\n","24:\"Pj2q\""],[20,"mRNA的最末端是聚腺苷化的。这是一种以「AAAAAAAAAAAAAAAAAAAAAA」的奇特结尾。"],[20,"\n","24:\"0bqn\""],[20,"\n","24:\"71Pu\""],[20,"似乎,就连mRNA似乎也受够了这个糟糕的2020年!"],[20,"\n","24:\"IlGa\""],[20,"\n","24:\"7SFz\""],[20,"mRNA可以重复使用很多次,但在这个过程中,它也会在末端失去一些A。一旦A耗尽,mRNA就不再起作用而被丢弃。这样,「多聚腺苷酸尾(Poly-A Tail)」就可以防止其退化。"],[20,"\n","24:\"1JVA\""],[20,"\n","24:\"qXT2\""],[20,"有研究表明,对于mRNA疫苗来说,A的最佳数量是多少。我在公开文献中读到,这个数字在120左右达到了顶峰。"],[20,"\n","24:\"F6Os\""],[20,"\n","24:\"Z67Q\""],[20,"BNT162b2疫苗的是:"],[20,"\n","24:\"ihrg\""],[20,"\n","24:\"7YX2\""],[20,{"gallery":"https://uploader.shimo.im/f/tusFvw4FJ0tIpcku.png!thumbnail"},"29:0|30:0|3:\"724\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"149\"|ori-width:\"724\""],[20,"\n","24:\"7QyT\""],[20,"\n","24:\"N36z\""],[20,"这是30个A,然后是「10个核苷酸连接体」(GCAUAUGACU),再后面是70个A。"],[20,"\n","24:\"69k4\""],[20,"\n","24:\"SqK1\""],[20,"总结"],[20,"\n","24:\"vwUI\"|heading:\"title\""],[20,"如果上面的一切让你感到云里雾里,作者在这里为您准备了一份「太长不看版」:"],[20,"\n","24:\"OQLJ\""],[20,"\n","24:\"tBD5\""],[20,"帽子来确保RNA看起来像普通的mRNA"],[20,"\n","24:\"iWYP\""],[20,"\n","24:\"P0FT\""],[20,"已知的成功和优化的5 ' UTR"],[20,"\n","24:\"2Ww5\""],[20,"\n","24:\"s1r6\""],[20,"密码子优化信号肽,将刺突蛋白送到正确的位置(100%从原始病毒复制)"],[20,"\n","24:\"pKRX\""],[20,"\n","24:\"ozvP\""],[20,"原始刺的密码子优化版本,有两个「脯氨酸」替代,以确保蛋白质以正确的形式出现"],[20,"\n","24:\"6box\""],[20,"\n","24:\"ccP0\""],[20,"一个已知的成功和优化的3 ' UTR"],[20,"\n","24:\"quj6\""],[20,"\n","24:\"6bWa\""],[20,"一个有点神秘的多聚腺苷酸尾(Poly-A Tail),里面有一个无法解释的「连接器」"],[20,"\n","24:\"GOHG\""],[20,"\n","24:\"AnWo\""],[20,"密码子优化在mRNA上增加了大量的G和C。与此同时,用ψ(1-甲基-3 ' -伪尿酰ψ)而不是U来帮助逃避我们的免疫系统,因此mRNA会停留足够长的时间,所以我们实际上可以帮助训练免疫系统。"],[20,"\n","24:\"h7hJ\""],[20,"\n","24:\"TTuP\""],[20,"\n","24:\"9BwE\""],[20,"\n","24:\"veIF\"|heading:\"title\""]]" style="letter-spacing: 0.544px; font-size: 15px;">听起来有些不可思议,但一位程序员从计算机科学的角度深度剖析了Biotech/辉瑞的mRNA新冠疫苗BNT162b设计,并撰写了这篇文章—— UUC)的修改都是同义的。疫苗的RNA编码不同,但会产生相同的氨基酸和蛋白质。"],[20,"\n","24:\"bUQk\""],[20,"\n","24:\"PTbn\""],[20,"如果我们仔细观察,我们会发现大部分的变化发生在密码子的第三个位置,上面有一个' 3 '。如果我们检查通用密码子表,我们会发现第三个位置通常与产生的氨基酸无关。"],[20,"\n","24:\"P6ah\""],[20,"\n","24:\"RKPu\""],[20,"所以,这些变化是同义的,但为什么会有这些变化呢?仔细观察,我们发现除了一个变化之外,所有的变化都会导致更多的C和G。"],[20,"\n","24:\"ZGRy\""],[20,"\n","24:\"ujmR\""],[20,"你为什么要这么做?如上所述,我们的免疫系统会对「外源性」RNA进行攻击,为了逃避检测,RNA中的「U」已经被ψ所取代了。"],[20,"\n","24:\"GYJ0\""],[20,"\n","24:\"i3b4\""],[20,"然而,事实证明,含有更多G和C的RNA也能更有效地转化为蛋白质,这已经在疫苗RNA中实现了只要有可能就用G和C替换许多字符。"],[20,"\n","24:\"xdD4\""],[20,"\n","24:\"aXIu\""],[20,"真正的刺突蛋白"],[20,"\n","24:\"OY8r\"|heading:\"title\""],[20,"\n","24:\"4jkI\""],[20,"疫苗RNA的下3777个字符类似于「密码子优化」,可以添加大量的C和G。"],[20,"\n","24:\"GP55\""],[20,"\n","24:\"mHHt\""],[20,{"gallery":"https://uploader.shimo.im/f/0bmEXwKd2EC33j3P.png!thumbnail"},"29:0|30:0|3:\"711\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"215\"|ori-width:\"711\""],[20,"\n","24:\"O7u7\""],[20,"\n","24:\"S6RY\""],[20,"这里我们看到同义的RNA变化。例如,在第一个密码子中CUU变成了CUG。这给疫苗增加了另一个「G」,我们知道这有助于提高蛋白质的生产。"],[20,"\n","24:\"kr4D\""],[20,"\n","24:\"qTAQ\""],[20,"当我们比较疫苗中的整个刺突蛋白时,所有的变化都是同义的。除了两个,这就是我们在这里看到的。"],[20,"\n","24:\"pnwO\""],[20,"\n","24:\"zGzF\""],[20,"上面的第三和第四个密码子代表了实际的变化。那里的K和V氨基酸都被P或脯氨酸所取代。对于「K」,这需要改变三次(「!!」),而对于「V」,这只需要改变两次(「!!」)。"],[20,"\n","24:\"Er2t\""],[20,"\n","24:\"lyjz\""],[20,"事实证明,这两个变化极大地提高了疫苗的效率。"],[20,"\n","24:\"kQPI\""],[20,"\n","24:\"o7BU\""],[20,"那么这里发生了什么?如果你看一个真正的冠状病毒粒子,你可以看到刺突蛋白:"],[20,"\n","24:\"3dSX\""],[20,"\n","24:\"4uyq\""],[20,{"gallery":"https://uploader.shimo.im/f/IS2OUFuSOlUJUMTw.png!thumbnail"},"29:0|30:0|3:\"943\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"672\"|ori-width:\"943\""],[20,"\n","24:\"hAu7\""],[20,"\n","24:\"QFV3\""],[20,"这些刺钉被安装在病毒体内(「核衣壳蛋白」)。但问题是,我们的疫苗只会产生刺突,我们不会把它们植入任何一种病毒体内。"],[20,"\n","24:\"sebh\""],[20,"\n","24:\"wC3y\""],[20,"结果是,未经修饰的,独立的刺突蛋白崩溃成不同的结构。如果作为疫苗注射,这确实会使我们的身体产生免疫力。但只针对崩溃的刺突蛋白。"],[20,"\n","24:\"Qba0\""],[20,"\n","24:\"m4p7\""],[20,"真正的冠状病毒是带着尖刺的。在这种情况下,疫苗不会很有效。"],[20,"\n","24:\"f2FP\""],[20,"\n","24:\"8JB8\""],[20,"那么该怎么办呢?"],[20,"\n","24:\"ICR5\""],[20,"\n","24:\"3H1H\""],[20,"2017年,有人描述了如何在正确的位置放置一个双脯氨酸替代,将使SARS-CoV-1和MERS S蛋白形成「预融合」结构,即使不是整个病毒的一部分。这是因为脯氨酸是一种非常坚硬的氨基酸。它就像一种夹板,在我们需要向免疫系统展示的状态下稳定蛋白质。"],[20,"\n","24:\"W3tM\""],[20,"\n","24:\"VnUj\""],[20,"蛋白质的末端,下一步"],[20,"\n","24:\"FAtJ\"|heading:\"title\""],[20,"\n","24:\"sTqb\""],[20,"如果我们浏览其余的源代码,我们会在刺突蛋白的末端遇到一些小的修改:"],[20,"\n","24:\"YbvU\""],[20,"\n","24:\"NRTt\""],[20,{"gallery":"https://uploader.shimo.im/f/hROE13Gv1eIb3OzF.png!thumbnail"},"29:0|30:0|3:\"727\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"197\"|ori-width:\"727\""],[20,"\n","24:\"oDYT\""],[20,"在蛋白质的末端,我们会发现一个「停止」密码子,在这里用小写的「s」表示。这是一种礼貌的说法,表示蛋白质应该到此为止。最初的病毒使用UAA终止密码子,疫苗使用两个UGA终止密码子,也许只是为了更好的措施。"],[20,"\n","24:\"OYg5\""],[20,"\n","24:\"oBiH\""],[20,"3 'UTR"],[20,"\n","24:\"Y1GI\"|heading:\"title\""],[20,"\n","24:\"TEnu\""],[20,"就像核糖体在5 '端需要引入,我们发现了' 5UTR,在蛋白质的末端我们发现了一个类似的结构,称为3 ' UTR。"],[20,"\n","24:\"kOrG\""],[20,"\n","24:\"0fad\""],[20,"关于3 ' UTR有很多说法,但这里引用维基百科的说法:「3 ' UTR在基因表达中起着至关重要的作用,它影响mRNA的定位、稳定性、输出和翻译效率。尽管我们目前对3 ' -UTRs有了解,但它们仍然是相对神秘的。」"],[20,"\n","24:\"Wlpy\""],[20,"\n","24:\"28nk\""],[20,"我们所知道的是,某些3 ' UTR在促进蛋白质表达方面非常成功。根据世卫组织的文件,辉瑞疫苗3 ' UTR是从「split (AES) mRNA的氨基末端增强子和编码12S核糖体RNA的线粒体中提取的,以保证RNA的稳定性和高总蛋白表达」。"],[20,"\n","24:\"4WmY\""],[20,"\n","24:\"or6H\""],[20,{"gallery":"https://uploader.shimo.im/f/7NO6x6dFyvuglDih.png!thumbnail"},"29:0|30:0|3:\"302\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"327\"|ori-width:\"302\""],[20,"\n","24:\"EbDX\""],[20,"\n","24:\"eYEy\""],[20,"The AAAAAAAAAAAAAAAAAAAAAA end of it all"],[20,"\n","24:\"noiV\"|heading:\"title\""],[20,"\n","24:\"Pj2q\""],[20,"mRNA的最末端是聚腺苷化的。这是一种以「AAAAAAAAAAAAAAAAAAAAAA」的奇特结尾。"],[20,"\n","24:\"0bqn\""],[20,"\n","24:\"71Pu\""],[20,"似乎,就连mRNA似乎也受够了这个糟糕的2020年!"],[20,"\n","24:\"IlGa\""],[20,"\n","24:\"7SFz\""],[20,"mRNA可以重复使用很多次,但在这个过程中,它也会在末端失去一些A。一旦A耗尽,mRNA就不再起作用而被丢弃。这样,「多聚腺苷酸尾(Poly-A Tail)」就可以防止其退化。"],[20,"\n","24:\"1JVA\""],[20,"\n","24:\"qXT2\""],[20,"有研究表明,对于mRNA疫苗来说,A的最佳数量是多少。我在公开文献中读到,这个数字在120左右达到了顶峰。"],[20,"\n","24:\"F6Os\""],[20,"\n","24:\"Z67Q\""],[20,"BNT162b2疫苗的是:"],[20,"\n","24:\"ihrg\""],[20,"\n","24:\"7YX2\""],[20,{"gallery":"https://uploader.shimo.im/f/tusFvw4FJ0tIpcku.png!thumbnail"},"29:0|30:0|3:\"724\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"149\"|ori-width:\"724\""],[20,"\n","24:\"7QyT\""],[20,"\n","24:\"N36z\""],[20,"这是30个A,然后是「10个核苷酸连接体」(GCAUAUGACU),再后面是70个A。"],[20,"\n","24:\"69k4\""],[20,"\n","24:\"SqK1\""],[20,"总结"],[20,"\n","24:\"vwUI\"|heading:\"title\""],[20,"如果上面的一切让你感到云里雾里,作者在这里为您准备了一份「太长不看版」:"],[20,"\n","24:\"OQLJ\""],[20,"\n","24:\"tBD5\""],[20,"帽子来确保RNA看起来像普通的mRNA"],[20,"\n","24:\"iWYP\""],[20,"\n","24:\"P0FT\""],[20,"已知的成功和优化的5 ' UTR"],[20,"\n","24:\"2Ww5\""],[20,"\n","24:\"s1r6\""],[20,"密码子优化信号肽,将刺突蛋白送到正确的位置(100%从原始病毒复制)"],[20,"\n","24:\"pKRX\""],[20,"\n","24:\"ozvP\""],[20,"原始刺的密码子优化版本,有两个「脯氨酸」替代,以确保蛋白质以正确的形式出现"],[20,"\n","24:\"6box\""],[20,"\n","24:\"ccP0\""],[20,"一个已知的成功和优化的3 ' UTR"],[20,"\n","24:\"quj6\""],[20,"\n","24:\"6bWa\""],[20,"一个有点神秘的多聚腺苷酸尾(Poly-A Tail),里面有一个无法解释的「连接器」"],[20,"\n","24:\"GOHG\""],[20,"\n","24:\"AnWo\""],[20,"密码子优化在mRNA上增加了大量的G和C。与此同时,用ψ(1-甲基-3 ' -伪尿酰ψ)而不是U来帮助逃避我们的免疫系统,因此mRNA会停留足够长的时间,所以我们实际上可以帮助训练免疫系统。"],[20,"\n","24:\"h7hJ\""],[20,"\n","24:\"TTuP\""],[20,"\n","24:\"9BwE\""],[20,"\n","24:\"veIF\"|heading:\"title\""]]" style="letter-spacing: 0.544px; font-size: 15px; color: rgb(255, 76, 0);">Biotech/辉瑞SARS-CoV-2疫苗的源代码的反向工程(Reverse Engineering the source code of the BioNTech/Pfizer SARS-CoV-2 Vaccine).(以下简称辉瑞疫苗)
读过后,你或许会开始会让你对生命和计算机世界产生奇妙的联系。
简单的生物学背景
让我们先来回顾一下生物学知识,这里,我们将透过程序员的眼睛看待生命编码。
DNA和程序的种种相似的地方,但与计算机使用0和1不同,生命使用A、C、G和U/T来编码。
在自然界中,A、C、G和U/T都是分子,以链的形式储存在DNA(或RNA)中。
在计算机中,我们把8位编入一个字节,字节是处理数据的典型单位。
自然界将3个核苷酸组合成一个密码子,而这个密码子是典型的处理单元。
密码子包含6位信息(每个DNA字符2位,3字符= 6位,这意味着2⁶ = 64种不同密码子值)。
其次,疫苗是一种液体,我们该如何谈论源代码?
源代码!
让我们从疫苗的一小部分源代码开始,下图为世界卫生组织公布的BNT162b前500个字符。
mRNA新冠疫苗BNT162b的核心就是这个数字代码。它有4284个字符长,在疫苗生产过程的最开始,将这段代码上传到DNA打印机,然后打印机将磁盘上的字节转换成实际的DNA分子。
DNA打印机,型号BioXp 3200
从这样的机器中产生了少量的DNA,在经过大量的生物和化学处理后,最终成为疫苗瓶中的RNA。
RNA就像计算机的RAM一样,但是,RNA非常脆弱,所以,辉瑞的mRNA疫苗必须储存在最深处的深冷库里。
每个RNA字符的重量为 0.53·10⁻²¹克,一针疫苗里有2万亿段重复的代码,相当于25 Pb的数据量。
让我 UUC)的修改都是同义的。疫苗的RNA编码不同,但会产生相同的氨基酸和蛋白质。"],[20,"\n","24:\"bUQk\""],[20,"\n","24:\"PTbn\""],[20,"如果我们仔细观察,我们会发现大部分的变化发生在密码子的第三个位置,上面有一个' 3 '。如果我们检查通用密码子表,我们会发现第三个位置通常与产生的氨基酸无关。"],[20,"\n","24:\"P6ah\""],[20,"\n","24:\"RKPu\""],[20,"所以,这些变化是同义的,但为什么会有这些变化呢?仔细观察,我们发现除了一个变化之外,所有的变化都会导致更多的C和G。"],[20,"\n","24:\"ZGRy\""],[20,"\n","24:\"ujmR\""],[20,"你为什么要这么做?如上所述,我们的免疫系统会对「外源性」RNA进行攻击,为了逃避检测,RNA中的「U」已经被ψ所取代了。"],[20,"\n","24:\"GYJ0\""],[20,"\n","24:\"i3b4\""],[20,"然而,事实证明,含有更多G和C的RNA也能更有效地转化为蛋白质,这已经在疫苗RNA中实现了只要有可能就用G和C替换许多字符。"],[20,"\n","24:\"xdD4\""],[20,"\n","24:\"aXIu\""],[20,"真正的刺突蛋白"],[20,"\n","24:\"OY8r\"|heading:\"title\""],[20,"\n","24:\"4jkI\""],[20,"疫苗RNA的下3777个字符类似于「密码子优化」,可以添加大量的C和G。"],[20,"\n","24:\"GP55\""],[20,"\n","24:\"mHHt\""],[20,{"gallery":"https://uploader.shimo.im/f/0bmEXwKd2EC33j3P.png!thumbnail"},"29:0|30:0|3:\"711\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"215\"|ori-width:\"711\""],[20,"\n","24:\"O7u7\""],[20,"\n","24:\"S6RY\""],[20,"这里我们看到同义的RNA变化。例如,在第一个密码子中CUU变成了CUG。这给疫苗增加了另一个「G」,我们知道这有助于提高蛋白质的生产。"],[20,"\n","24:\"kr4D\""],[20,"\n","24:\"qTAQ\""],[20,"当我们比较疫苗中的整个刺突蛋白时,所有的变化都是同义的。除了两个,这就是我们在这里看到的。"],[20,"\n","24:\"pnwO\""],[20,"\n","24:\"zGzF\""],[20,"上面的第三和第四个密码子代表了实际的变化。那里的K和V氨基酸都被P或脯氨酸所取代。对于「K」,这需要改变三次(「!!」),而对于「V」,这只需要改变两次(「!!」)。"],[20,"\n","24:\"Er2t\""],[20,"\n","24:\"lyjz\""],[20,"事实证明,这两个变化极大地提高了疫苗的效率。"],[20,"\n","24:\"kQPI\""],[20,"\n","24:\"o7BU\""],[20,"那么这里发生了什么?如果你看一个真正的冠状病毒粒子,你可以看到刺突蛋白:"],[20,"\n","24:\"3dSX\""],[20,"\n","24:\"4uyq\""],[20,{"gallery":"https://uploader.shimo.im/f/IS2OUFuSOlUJUMTw.png!thumbnail"},"29:0|30:0|3:\"943\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"672\"|ori-width:\"943\""],[20,"\n","24:\"hAu7\""],[20,"\n","24:\"QFV3\""],[20,"这些刺钉被安装在病毒体内(「核衣壳蛋白」)。但问题是,我们的疫苗只会产生刺突,我们不会把它们植入任何一种病毒体内。"],[20,"\n","24:\"sebh\""],[20,"\n","24:\"wC3y\""],[20,"结果是,未经修饰的,独立的刺突蛋白崩溃成不同的结构。如果作为疫苗注射,这确实会使我们的身体产生免疫力。但只针对崩溃的刺突蛋白。"],[20,"\n","24:\"Qba0\""],[20,"\n","24:\"m4p7\""],[20,"真正的冠状病毒是带着尖刺的。在这种情况下,疫苗不会很有效。"],[20,"\n","24:\"f2FP\""],[20,"\n","24:\"8JB8\""],[20,"那么该怎么办呢?"],[20,"\n","24:\"ICR5\""],[20,"\n","24:\"3H1H\""],[20,"2017年,有人描述了如何在正确的位置放置一个双脯氨酸替代,将使SARS-CoV-1和MERS S蛋白形成「预融合」结构,即使不是整个病毒的一部分。这是因为脯氨酸是一种非常坚硬的氨基酸。它就像一种夹板,在我们需要向免疫系统展示的状态下稳定蛋白质。"],[20,"\n","24:\"W3tM\""],[20,"\n","24:\"VnUj\""],[20,"蛋白质的末端,下一步"],[20,"\n","24:\"FAtJ\"|heading:\"title\""],[20,"\n","24:\"sTqb\""],[20,"如果我们浏览其余的源代码,我们会在刺突蛋白的末端遇到一些小的修改:"],[20,"\n","24:\"YbvU\""],[20,"\n","24:\"NRTt\""],[20,{"gallery":"https://uploader.shimo.im/f/hROE13Gv1eIb3OzF.png!thumbnail"},"29:0|30:0|3:\"727\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"197\"|ori-width:\"727\""],[20,"\n","24:\"oDYT\""],[20,"在蛋白质的末端,我们会发现一个「停止」密码子,在这里用小写的「s」表示。这是一种礼貌的说法,表示蛋白质应该到此为止。最初的病毒使用UAA终止密码子,疫苗使用两个UGA终止密码子,也许只是为了更好的措施。"],[20,"\n","24:\"OYg5\""],[20,"\n","24:\"oBiH\""],[20,"3 'UTR"],[20,"\n","24:\"Y1GI\"|heading:\"title\""],[20,"\n","24:\"TEnu\""],[20,"就像核糖体在5 '端需要引入,我们发现了' 5UTR,在蛋白质的末端我们发现了一个类似的结构,称为3 ' UTR。"],[20,"\n","24:\"kOrG\""],[20,"\n","24:\"0fad\""],[20,"关于3 ' UTR有很多说法,但这里引用维基百科的说法:「3 ' UTR在基因表达中起着至关重要的作用,它影响mRNA的定位、稳定性、输出和翻译效率。尽管我们目前对3 ' -UTRs有了解,但它们仍然是相对神秘的。」"],[20,"\n","24:\"Wlpy\""],[20,"\n","24:\"28nk\""],[20,"我们所知道的是,某些3 ' UTR在促进蛋白质表达方面非常成功。根据世卫组织的文件,辉瑞疫苗3 ' UTR是从「split (AES) mRNA的氨基末端增强子和编码12S核糖体RNA的线粒体中提取的,以保证RNA的稳定性和高总蛋白表达」。"],[20,"\n","24:\"4WmY\""],[20,"\n","24:\"or6H\""],[20,{"gallery":"https://uploader.shimo.im/f/7NO6x6dFyvuglDih.png!thumbnail"},"29:0|30:0|3:\"302\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"327\"|ori-width:\"302\""],[20,"\n","24:\"EbDX\""],[20,"\n","24:\"eYEy\""],[20,"The AAAAAAAAAAAAAAAAAAAAAA end of it all"],[20,"\n","24:\"noiV\"|heading:\"title\""],[20,"\n","24:\"Pj2q\""],[20,"mRNA的最末端是聚腺苷化的。这是一种以「AAAAAAAAAAAAAAAAAAAAAA」的奇特结尾。"],[20,"\n","24:\"0bqn\""],[20,"\n","24:\"71Pu\""],[20,"似乎,就连mRNA似乎也受够了这个糟糕的2020年!"],[20,"\n","24:\"IlGa\""],[20,"\n","24:\"7SFz\""],[20,"mRNA可以重复使用很多次,但在这个过程中,它也会在末端失去一些A。一旦A耗尽,mRNA就不再起作用而被丢弃。这样,「多聚腺苷酸尾(Poly-A Tail)」就可以防止其退化。"],[20,"\n","24:\"1JVA\""],[20,"\n","24:\"qXT2\""],[20,"有研究表明,对于mRNA疫苗来说,A的最佳数量是多少。我在公开文献中读到,这个数字在120左右达到了顶峰。"],[20,"\n","24:\"F6Os\""],[20,"\n","24:\"Z67Q\""],[20,"BNT162b2疫苗的是:"],[20,"\n","24:\"ihrg\""],[20,"\n","24:\"7YX2\""],[20,{"gallery":"https://uploader.shimo.im/f/tusFvw4FJ0tIpcku.png!thumbnail"},"29:0|30:0|3:\"724\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"149\"|ori-width:\"724\""],[20,"\n","24:\"7QyT\""],[20,"\n","24:\"N36z\""],[20,"这是30个A,然后是「10个核苷酸连接体」(GCAUAUGACU),再后面是70个A。"],[20,"\n","24:\"69k4\""],[20,"\n","24:\"SqK1\""],[20,"总结"],[20,"\n","24:\"vwUI\"|heading:\"title\""],[20,"如果上面的一切让你感到云里雾里,作者在这里为您准备了一份「太长不看版」:"],[20,"\n","24:\"OQLJ\""],[20,"\n","24:\"tBD5\""],[20,"帽子来确保RNA看起来像普通的mRNA"],[20,"\n","24:\"iWYP\""],[20,"\n","24:\"P0FT\""],[20,"已知的成功和优化的5 ' UTR"],[20,"\n","24:\"2Ww5\""],[20,"\n","24:\"s1r6\""],[20,"密码子优化信号肽,将刺突蛋白送到正确的位置(100%从原始病毒复制)"],[20,"\n","24:\"pKRX\""],[20,"\n","24:\"ozvP\""],[20,"原始刺的密码子优化版本,有两个「脯氨酸」替代,以确保蛋白质以正确的形式出现"],[20,"\n","24:\"6box\""],[20,"\n","24:\"ccP0\""],[20,"一个已知的成功和优化的3 ' UTR"],[20,"\n","24:\"quj6\""],[20,"\n","24:\"6bWa\""],[20,"一个有点神秘的多聚腺苷酸尾(Poly-A Tail),里面有一个无法解释的「连接器」"],[20,"\n","24:\"GOHG\""],[20,"\n","24:\"AnWo\""],[20,"密码子优化在mRNA上增加了大量的G和C。与此同时,用ψ(1-甲基-3 ' -伪尿酰ψ)而不是U来帮助逃避我们的免疫系统,因此mRNA会停留足够长的时间,所以我们实际上可以帮助训练免疫系统。"],[20,"\n","24:\"h7hJ\""],[20,"\n","24:\"TTuP\""],[20,"\n","24:\"9BwE\""],[20,"\n","24:\"veIF\"|heading:\"title\""]]" style="font-size: 15px; letter-spacing: 1px;">们来看世卫组织文件披露的一页:
首先,cap是什么?就像你不能在计算机上的一个文件中输入操作码然后运行它一样,生物操作系统需要头文件、链接器和调用约定之类的东西。
疫苗的编码由以下两个核苷酸开始:
这可以与以MZ开头的DOS和Windows可执行文件,或以#!开头的UNIX脚本进行比较。在生活系统和操作系统中,这两个字符都不会以任何方式执行。但他们必须在那里,否则什么都不会发生。
mRNA 「帽」有许多功能,它让代码看起来合法,从而保护它不被我们身体里的免疫系统破坏。
未翻译区5 'UTR
未翻译区5 'UTR
生命由蛋白质组成。当RNA转化为蛋白质时,这被称为翻译。
RNA分子只能从一个方向读取。令人困惑的是,阅读开始的部分被称为 UUC)的修改都是同义的。疫苗的RNA编码不同,但会产生相同的氨基酸和蛋白质。"],[20,"\n","24:\"bUQk\""],[20,"\n","24:\"PTbn\""],[20,"如果我们仔细观察,我们会发现大部分的变化发生在密码子的第三个位置,上面有一个' 3 '。如果我们检查通用密码子表,我们会发现第三个位置通常与产生的氨基酸无关。"],[20,"\n","24:\"P6ah\""],[20,"\n","24:\"RKPu\""],[20,"所以,这些变化是同义的,但为什么会有这些变化呢?仔细观察,我们发现除了一个变化之外,所有的变化都会导致更多的C和G。"],[20,"\n","24:\"ZGRy\""],[20,"\n","24:\"ujmR\""],[20,"你为什么要这么做?如上所述,我们的免疫系统会对「外源性」RNA进行攻击,为了逃避检测,RNA中的「U」已经被ψ所取代了。"],[20,"\n","24:\"GYJ0\""],[20,"\n","24:\"i3b4\""],[20,"然而,事实证明,含有更多G和C的RNA也能更有效地转化为蛋白质,这已经在疫苗RNA中实现了只要有可能就用G和C替换许多字符。"],[20,"\n","24:\"xdD4\""],[20,"\n","24:\"aXIu\""],[20,"真正的刺突蛋白"],[20,"\n","24:\"OY8r\"|heading:\"title\""],[20,"\n","24:\"4jkI\""],[20,"疫苗RNA的下3777个字符类似于「密码子优化」,可以添加大量的C和G。"],[20,"\n","24:\"GP55\""],[20,"\n","24:\"mHHt\""],[20,{"gallery":"https://uploader.shimo.im/f/0bmEXwKd2EC33j3P.png!thumbnail"},"29:0|30:0|3:\"711\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"215\"|ori-width:\"711\""],[20,"\n","24:\"O7u7\""],[20,"\n","24:\"S6RY\""],[20,"这里我们看到同义的RNA变化。例如,在第一个密码子中CUU变成了CUG。这给疫苗增加了另一个「G」,我们知道这有助于提高蛋白质的生产。"],[20,"\n","24:\"kr4D\""],[20,"\n","24:\"qTAQ\""],[20,"当我们比较疫苗中的整个刺突蛋白时,所有的变化都是同义的。除了两个,这就是我们在这里看到的。"],[20,"\n","24:\"pnwO\""],[20,"\n","24:\"zGzF\""],[20,"上面的第三和第四个密码子代表了实际的变化。那里的K和V氨基酸都被P或脯氨酸所取代。对于「K」,这需要改变三次(「!!」),而对于「V」,这只需要改变两次(「!!」)。"],[20,"\n","24:\"Er2t\""],[20,"\n","24:\"lyjz\""],[20,"事实证明,这两个变化极大地提高了疫苗的效率。"],[20,"\n","24:\"kQPI\""],[20,"\n","24:\"o7BU\""],[20,"那么这里发生了什么?如果你看一个真正的冠状病毒粒子,你可以看到刺突蛋白:"],[20,"\n","24:\"3dSX\""],[20,"\n","24:\"4uyq\""],[20,{"gallery":"https://uploader.shimo.im/f/IS2OUFuSOlUJUMTw.png!thumbnail"},"29:0|30:0|3:\"943\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"672\"|ori-width:\"943\""],[20,"\n","24:\"hAu7\""],[20,"\n","24:\"QFV3\""],[20,"这些刺钉被安装在病毒体内(「核衣壳蛋白」)。但问题是,我们的疫苗只会产生刺突,我们不会把它们植入任何一种病毒体内。"],[20,"\n","24:\"sebh\""],[20,"\n","24:\"wC3y\""],[20,"结果是,未经修饰的,独立的刺突蛋白崩溃成不同的结构。如果作为疫苗注射,这确实会使我们的身体产生免疫力。但只针对崩溃的刺突蛋白。"],[20,"\n","24:\"Qba0\""],[20,"\n","24:\"m4p7\""],[20,"真正的冠状病毒是带着尖刺的。在这种情况下,疫苗不会很有效。"],[20,"\n","24:\"f2FP\""],[20,"\n","24:\"8JB8\""],[20,"那么该怎么办呢?"],[20,"\n","24:\"ICR5\""],[20,"\n","24:\"3H1H\""],[20,"2017年,有人描述了如何在正确的位置放置一个双脯氨酸替代,将使SARS-CoV-1和MERS S蛋白形成「预融合」结构,即使不是整个病毒的一部分。这是因为脯氨酸是一种非常坚硬的氨基酸。它就像一种夹板,在我们需要向免疫系统展示的状态下稳定蛋白质。"],[20,"\n","24:\"W3tM\""],[20,"\n","24:\"VnUj\""],[20,"蛋白质的末端,下一步"],[20,"\n","24:\"FAtJ\"|heading:\"title\""],[20,"\n","24:\"sTqb\""],[20,"如果我们浏览其余的源代码,我们会在刺突蛋白的末端遇到一些小的修改:"],[20,"\n","24:\"YbvU\""],[20,"\n","24:\"NRTt\""],[20,{"gallery":"https://uploader.shimo.im/f/hROE13Gv1eIb3OzF.png!thumbnail"},"29:0|30:0|3:\"727\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"197\"|ori-width:\"727\""],[20,"\n","24:\"oDYT\""],[20,"在蛋白质的末端,我们会发现一个「停止」密码子,在这里用小写的「s」表示。这是一种礼貌的说法,表示蛋白质应该到此为止。最初的病毒使用UAA终止密码子,疫苗使用两个UGA终止密码子,也许只是为了更好的措施。"],[20,"\n","24:\"OYg5\""],[20,"\n","24:\"oBiH\""],[20,"3 'UTR"],[20,"\n","24:\"Y1GI\"|heading:\"title\""],[20,"\n","24:\"TEnu\""],[20,"就像核糖体在5 '端需要引入,我们发现了' 5UTR,在蛋白质的末端我们发现了一个类似的结构,称为3 ' UTR。"],[20,"\n","24:\"kOrG\""],[20,"\n","24:\"0fad\""],[20,"关于3 ' UTR有很多说法,但这里引用维基百科的说法:「3 ' UTR在基因表达中起着至关重要的作用,它影响mRNA的定位、稳定性、输出和翻译效率。尽管我们目前对3 ' -UTRs有了解,但它们仍然是相对神秘的。」"],[20,"\n","24:\"Wlpy\""],[20,"\n","24:\"28nk\""],[20,"我们所知道的是,某些3 ' UTR在促进蛋白质表达方面非常成功。根据世卫组织的文件,辉瑞疫苗3 ' UTR是从「split (AES) mRNA的氨基末端增强子和编码12S核糖体RNA的线粒体中提取的,以保证RNA的稳定性和高总蛋白表达」。"],[20,"\n","24:\"4WmY\""],[20,"\n","24:\"or6H\""],[20,{"gallery":"https://uploader.shimo.im/f/7NO6x6dFyvuglDih.png!thumbnail"},"29:0|30:0|3:\"302\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"327\"|ori-width:\"302\""],[20,"\n","24:\"EbDX\""],[20,"\n","24:\"eYEy\""],[20,"The AAAAAAAAAAAAAAAAAAAAAA end of it all"],[20,"\n","24:\"noiV\"|heading:\"title\""],[20,"\n","24:\"Pj2q\""],[20,"mRNA的最末端是聚腺苷化的。这是一种以「AAAAAAAAAAAAAAAAAAAAAA」的奇特结尾。"],[20,"\n","24:\"0bqn\""],[20,"\n","24:\"71Pu\""],[20,"似乎,就连mRNA似乎也受够了这个糟糕的2020年!"],[20,"\n","24:\"IlGa\""],[20,"\n","24:\"7SFz\""],[20,"mRNA可以重复使用很多次,但在这个过程中,它也会在末端失去一些A。一旦A耗尽,mRNA就不再起作用而被丢弃。这样,「多聚腺苷酸尾(Poly-A Tail)」就可以防止其退化。"],[20,"\n","24:\"1JVA\""],[20,"\n","24:\"qXT2\""],[20,"有研究表明,对于mRNA疫苗来说,A的最佳数量是多少。我在公开文献中读到,这个数字在120左右达到了顶峰。"],[20,"\n","24:\"F6Os\""],[20,"\n","24:\"Z67Q\""],[20,"BNT162b2疫苗的是:"],[20,"\n","24:\"ihrg\""],[20,"\n","24:\"7YX2\""],[20,{"gallery":"https://uploader.shimo.im/f/tusFvw4FJ0tIpcku.png!thumbnail"},"29:0|30:0|3:\"724\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"149\"|ori-width:\"724\""],[20,"\n","24:\"7QyT\""],[20,"\n","24:\"N36z\""],[20,"这是30个A,然后是「10个核苷酸连接体」(GCAUAUGACU),再后面是70个A。"],[20,"\n","24:\"69k4\""],[20,"\n","24:\"SqK1\""],[20,"总结"],[20,"\n","24:\"vwUI\"|heading:\"title\""],[20,"如果上面的一切让你感到云里雾里,作者在这里为您准备了一份「太长不看版」:"],[20,"\n","24:\"OQLJ\""],[20,"\n","24:\"tBD5\""],[20,"帽子来确保RNA看起来像普通的mRNA"],[20,"\n","24:\"iWYP\""],[20,"\n","24:\"P0FT\""],[20,"已知的成功和优化的5 ' UTR"],[20,"\n","24:\"2Ww5\""],[20,"\n","24:\"s1r6\""],[20,"密码子优化信号肽,将刺突蛋白送到正确的位置(100%从原始病毒复制)"],[20,"\n","24:\"pKRX\""],[20,"\n","24:\"ozvP\""],[20,"原始刺的密码子优化版本,有两个「脯氨酸」替代,以确保蛋白质以正确的形式出现"],[20,"\n","24:\"6box\""],[20,"\n","24:\"ccP0\""],[20,"一个已知的成功和优化的3 ' UTR"],[20,"\n","24:\"quj6\""],[20,"\n","24:\"6bWa\""],[20,"一个有点神秘的多聚腺苷酸尾(Poly-A Tail),里面有一个无法解释的「连接器」"],[20,"\n","24:\"GOHG\""],[20,"\n","24:\"AnWo\""],[20,"密码子优化在mRNA上增加了大量的G和C。与此同时,用ψ(1-甲基-3 ' -伪尿酰ψ)而不是U来帮助逃避我们的免疫系统,因此mRNA会停留足够长的时间,所以我们实际上可以帮助训练免疫系统。"],[20,"\n","24:\"h7hJ\""],[20,"\n","24:\"TTuP\""],[20,"\n","24:\"9BwE\""],[20,"\n","24:\"veIF\"|heading:\"title\""]]" style="font-size: 15px; letter-spacing: 1px;">5 UUC)的修改都是同义的。疫苗的RNA编码不同,但会产生相同的氨基酸和蛋白质。"],[20,"\n","24:\"bUQk\""],[20,"\n","24:\"PTbn\""],[20,"如果我们仔细观察,我们会发现大部分的变化发生在密码子的第三个位置,上面有一个' 3 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'。如果我们检查通用密码子表,我们会发现第三个位置通常与产生的氨基酸无关。"],[20,"\n","24:\"P6ah\""],[20,"\n","24:\"RKPu\""],[20,"所以,这些变化是同义的,但为什么会有这些变化呢?仔细观察,我们发现除了一个变化之外,所有的变化都会导致更多的C和G。"],[20,"\n","24:\"ZGRy\""],[20,"\n","24:\"ujmR\""],[20,"你为什么要这么做?如上所述,我们的免疫系统会对「外源性」RNA进行攻击,为了逃避检测,RNA中的「U」已经被ψ所取代了。"],[20,"\n","24:\"GYJ0\""],[20,"\n","24:\"i3b4\""],[20,"然而,事实证明,含有更多G和C的RNA也能更有效地转化为蛋白质,这已经在疫苗RNA中实现了只要有可能就用G和C替换许多字符。"],[20,"\n","24:\"xdD4\""],[20,"\n","24:\"aXIu\""],[20,"真正的刺突蛋白"],[20,"\n","24:\"OY8r\"|heading:\"title\""],[20,"\n","24:\"4jkI\""],[20,"疫苗RNA的下3777个字符类似于「密码子优化」,可以添加大量的C和G。"],[20,"\n","24:\"GP55\""],[20,"\n","24:\"mHHt\""],[20,{"gallery":"https://uploader.shimo.im/f/0bmEXwKd2EC33j3P.png!thumbnail"},"29:0|30:0|3:\"711\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"215\"|ori-width:\"711\""],[20,"\n","24:\"O7u7\""],[20,"\n","24:\"S6RY\""],[20,"这里我们看到同义的RNA变化。例如,在第一个密码子中CUU变成了CUG。这给疫苗增加了另一个「G」,我们知道这有助于提高蛋白质的生产。"],[20,"\n","24:\"kr4D\""],[20,"\n","24:\"qTAQ\""],[20,"当我们比较疫苗中的整个刺突蛋白时,所有的变化都是同义的。除了两个,这就是我们在这里看到的。"],[20,"\n","24:\"pnwO\""],[20,"\n","24:\"zGzF\""],[20,"上面的第三和第四个密码子代表了实际的变化。那里的K和V氨基酸都被P或脯氨酸所取代。对于「K」,这需要改变三次(「!!」),而对于「V」,这只需要改变两次(「!!」)。"],[20,"\n","24:\"Er2t\""],[20,"\n","24:\"lyjz\""],[20,"事实证明,这两个变化极大地提高了疫苗的效率。"],[20,"\n","24:\"kQPI\""],[20,"\n","24:\"o7BU\""],[20,"那么这里发生了什么?如果你看一个真正的冠状病毒粒子,你可以看到刺突蛋白:"],[20,"\n","24:\"3dSX\""],[20,"\n","24:\"4uyq\""],[20,{"gallery":"https://uploader.shimo.im/f/IS2OUFuSOlUJUMTw.png!thumbnail"},"29:0|30:0|3:\"943\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"672\"|ori-width:\"943\""],[20,"\n","24:\"hAu7\""],[20,"\n","24:\"QFV3\""],[20,"这些刺钉被安装在病毒体内(「核衣壳蛋白」)。但问题是,我们的疫苗只会产生刺突,我们不会把它们植入任何一种病毒体内。"],[20,"\n","24:\"sebh\""],[20,"\n","24:\"wC3y\""],[20,"结果是,未经修饰的,独立的刺突蛋白崩溃成不同的结构。如果作为疫苗注射,这确实会使我们的身体产生免疫力。但只针对崩溃的刺突蛋白。"],[20,"\n","24:\"Qba0\""],[20,"\n","24:\"m4p7\""],[20,"真正的冠状病毒是带着尖刺的。在这种情况下,疫苗不会很有效。"],[20,"\n","24:\"f2FP\""],[20,"\n","24:\"8JB8\""],[20,"那么该怎么办呢?"],[20,"\n","24:\"ICR5\""],[20,"\n","24:\"3H1H\""],[20,"2017年,有人描述了如何在正确的位置放置一个双脯氨酸替代,将使SARS-CoV-1和MERS S蛋白形成「预融合」结构,即使不是整个病毒的一部分。这是因为脯氨酸是一种非常坚硬的氨基酸。它就像一种夹板,在我们需要向免疫系统展示的状态下稳定蛋白质。"],[20,"\n","24:\"W3tM\""],[20,"\n","24:\"VnUj\""],[20,"蛋白质的末端,下一步"],[20,"\n","24:\"FAtJ\"|heading:\"title\""],[20,"\n","24:\"sTqb\""],[20,"如果我们浏览其余的源代码,我们会在刺突蛋白的末端遇到一些小的修改:"],[20,"\n","24:\"YbvU\""],[20,"\n","24:\"NRTt\""],[20,{"gallery":"https://uploader.shimo.im/f/hROE13Gv1eIb3OzF.png!thumbnail"},"29:0|30:0|3:\"727\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"197\"|ori-width:\"727\""],[20,"\n","24:\"oDYT\""],[20,"在蛋白质的末端,我们会发现一个「停止」密码子,在这里用小写的「s」表示。这是一种礼貌的说法,表示蛋白质应该到此为止。最初的病毒使用UAA终止密码子,疫苗使用两个UGA终止密码子,也许只是为了更好的措施。"],[20,"\n","24:\"OYg5\""],[20,"\n","24:\"oBiH\""],[20,"3 'UTR"],[20,"\n","24:\"Y1GI\"|heading:\"title\""],[20,"\n","24:\"TEnu\""],[20,"就像核糖体在5 '端需要引入,我们发现了' 5UTR,在蛋白质的末端我们发现了一个类似的结构,称为3 ' UTR。"],[20,"\n","24:\"kOrG\""],[20,"\n","24:\"0fad\""],[20,"关于3 ' UTR有很多说法,但这里引用维基百科的说法:「3 ' UTR在基因表达中起着至关重要的作用,它影响mRNA的定位、稳定性、输出和翻译效率。尽管我们目前对3 ' -UTRs有了解,但它们仍然是相对神秘的。」"],[20,"\n","24:\"Wlpy\""],[20,"\n","24:\"28nk\""],[20,"我们所知道的是,某些3 ' UTR在促进蛋白质表达方面非常成功。根据世卫组织的文件,辉瑞疫苗3 ' UTR是从「split (AES) mRNA的氨基末端增强子和编码12S核糖体RNA的线粒体中提取的,以保证RNA的稳定性和高总蛋白表达」。"],[20,"\n","24:\"4WmY\""],[20,"\n","24:\"or6H\""],[20,{"gallery":"https://uploader.shimo.im/f/7NO6x6dFyvuglDih.png!thumbnail"},"29:0|30:0|3:\"302\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"327\"|ori-width:\"302\""],[20,"\n","24:\"EbDX\""],[20,"\n","24:\"eYEy\""],[20,"The AAAAAAAAAAAAAAAAAAAAAA end of it all"],[20,"\n","24:\"noiV\"|heading:\"title\""],[20,"\n","24:\"Pj2q\""],[20,"mRNA的最末端是聚腺苷化的。这是一种以「AAAAAAAAAAAAAAAAAAAAAA」的奇特结尾。"],[20,"\n","24:\"0bqn\""],[20,"\n","24:\"71Pu\""],[20,"似乎,就连mRNA似乎也受够了这个糟糕的2020年!"],[20,"\n","24:\"IlGa\""],[20,"\n","24:\"7SFz\""],[20,"mRNA可以重复使用很多次,但在这个过程中,它也会在末端失去一些A。一旦A耗尽,mRNA就不再起作用而被丢弃。这样,「多聚腺苷酸尾(Poly-A Tail)」就可以防止其退化。"],[20,"\n","24:\"1JVA\""],[20,"\n","24:\"qXT2\""],[20,"有研究表明,对于mRNA疫苗来说,A的最佳数量是多少。我在公开文献中读到,这个数字在120左右达到了顶峰。"],[20,"\n","24:\"F6Os\""],[20,"\n","24:\"Z67Q\""],[20,"BNT162b2疫苗的是:"],[20,"\n","24:\"ihrg\""],[20,"\n","24:\"7YX2\""],[20,{"gallery":"https://uploader.shimo.im/f/tusFvw4FJ0tIpcku.png!thumbnail"},"29:0|30:0|3:\"724\"|4:\"auto\"|crop:\"\"|frame:\"none\"|ori-height:\"149\"|ori-width:\"724\""],[20,"\n","24:\"7QyT\""],[20,"\n","24:\"N36z\""],[20,"这是30个A,然后是「10个核苷酸连接体」(GCAUAUGACU),再后面是70个A。"],[20,"\n","24:\"69k4\""],[20,"\n","24:\"SqK1\""],[20,"总结"],[20,"\n","24:\"vwUI\"|heading:\"title\""],[20,"如果上面的一切让你感到云里雾里,作者在这里为您准备了一份「太长不看版」:"],[20,"\n","24:\"OQLJ\""],[20,"\n","24:\"tBD5\""],[20,"帽子来确保RNA看起来像普通的mRNA"],[20,"\n","24:\"iWYP\""],[20,"\n","24:\"P0FT\""],[20,"已知的成功和优化的5 ' UTR"],[20,"\n","24:\"2Ww5\""],[20,"\n","24:\"s1r6\""],[20,"密码子优化信号肽,将刺突蛋白送到正确的位置(100%从原始病毒复制)"],[20,"\n","24:\"pKRX\""],[20,"\n","24:\"ozvP\""],[20,"原始刺的密码子优化版本,有两个「脯氨酸」替代,以确保蛋白质以正确的形式出现"],[20,"\n","24:\"6box\""],[20,"\n","24:\"ccP0\""],[20,"一个已知的成功和优化的3 ' UTR"],[20,"\n","24:\"quj6\""],[20,"\n","24:\"6bWa\""],[20,"一个有点神秘的多聚腺苷酸尾(Poly-A Tail),里面有一个无法解释的「连接器」"],[20,"\n","24:\"GOHG\""],[20,"\n","24:\"AnWo\""],[20,"密码子优化在mRNA上增加了大量的G和C。与此同时,用ψ(1-甲基-3 ' -伪尿酰ψ)而不是U来帮助逃避我们的免疫系统,因此mRNA会停留足够长的时间,所以我们实际上可以帮助训练免疫系统。"],[20,"\n","24:\"h7hJ\""],[20,"\n","24:\"TTuP\""],[20,"\n","24:\"9BwE\""],[20,"\n","24:\"veIF\"|heading:\"title\""]]" style="font-size: 15px; letter-spacing: 1px;">'UTR停止。
UTR(Untranslated Regions)即非翻译区,是mRNA分子两端的非编码片段:
在这里,我们遇到了第一个惊喜。正常的RNA特征是A、C、G和U。U在DNA中也被称为「T」。但在这里我们发现了一个ψ。
怎么回事?
这是关于疫苗的一个特别聪明的地方。我们的身体运行着一个强大的反病毒系统,由于这个原因,细胞对外来RNA非常冷淡,并且在它做出任何反应之前就要破坏它。
这对我们的疫苗来说是个问题——它需要偷偷通过我们的免疫系统。经过多年的实验,人们发现,如果RNA中的U被一种稍作修饰的分子所取代,我们的免疫系统就会失去兴趣。
所以在辉瑞疫苗中,每个U都被1-甲基-3 ' -伪尿酰(ψ)所取代,它能帮助我们的疫苗逃过免疫系统这一关。
在计算机安全领域,我们也知道这个诀窍:有时可能传输某样东西,虽然这会引起防火墙和安全解决方案的怀疑,但这仍然被后端服务器接受,然后可能被黑客攻击。
很多人问,病毒能否也用ψ技术来打败我们的免疫系统?
这是不太可能的。因为生命根本没有制造1-甲基-3 ' -伪尿酰核苷酸的机制,而病毒需要依靠生命的机制来繁殖自己。而mRNA疫苗在人体内迅速降解,而ψ修饰后的RNA不可能在那里复制。
回到5 ' UTR。这51个字符是做什么的?如同自然界的一切事物一样,几乎没有任何事物有一个明确的功能。
当我们的细胞需要将RNA翻译成蛋白质时,这需要使用一种叫做核糖体的机器。核糖体就像蛋白质的3D打印机。它摄取一串RNA,在此基础上释放出一串氨基酸,然后折叠成蛋白质。
这就是我们在上面看到的情况。底部的黑色丝带是RNA。出现在绿色部分的缎带是正在形成的蛋白质。进出的东西是氨基酸和使它们适合RNA的适配器。
这个核糖体需要坐在RNA链上才能发挥作用。一旦就位,它就可以开始根据它摄入的RNA进一步形成蛋白质。从这一点上,你可以想象它还不能读出它首先降落的地方。
这只是UTR的功能之一:核糖体着陆区。UTR提供「导入」。
S糖蛋白信号肽
如前所述,疫苗的目标是让细胞产生大量刺突蛋白。到目前为止,我们在疫苗源代码中遇到的大多是元数据和调用约定。现在我们进入病毒蛋白质的领域。
然而,我们还有一层元数据需要处理。一旦核糖体制造出一个蛋白质,这个蛋白质仍然需要去某个地方。这是编码在「S糖蛋白信号肽(扩展先导序列)」。
了解这一点的方法是,在蛋白质的开头有一种地址标签,作为蛋白质本身编码的一部分。在这个特定的例子中,信号肽表明这种蛋白质应该通过「内质网」离开细胞。
「信号肽」不是很长,但是当我们看代码时,病毒和疫苗的RNA是有区别的:
怎么回事呢?我们知道,在生物学中,三个RNA字符组成一个密码子。每个密码子都对特定的氨基酸进行编码。而疫苗中的信号肽与病毒本身的氨基酸完全相同。
那么RNA是怎么不同的呢?
有4³=64个不同的密码子,因为有4个RNA字符,一个密码子中有3个。然而只有20种不同的氨基酸。这意味着多个密码子对同一种氨基酸进行编码。
下表映射了RNA密码子和氨基酸之间的编码关系:
RNA密码子表(维基百科)
在这个表中,我们可以看到疫苗(UUU -> UUC)的修改都是同义的。疫苗的RNA编码不同,但会产生相同的氨基酸和蛋白质。
如果我们仔细观察,我们会发现大部分的变化发生在密码子的第三个位置,上面有一个' 3 '。如果我们检查通用密码子表,我们会发现第三个位置通常与产生的氨基酸无关。
所以,这些变化是同义的,但为什么会有这些变化呢?仔细观察,我们发现除了一个变化之外,所有的变化都会导致更多的C和G。
你为什么要这么做?如上所述,我们的免疫系统会对「外源性」RNA进行攻击,为了逃避检测,RNA中的「U」已经被ψ所取代了。
然而,事实证明,含有更多G和C的RNA也能更有效地转化为蛋白质,这已经在疫苗RNA中实现了只要有可能就用G和C替换许多字符。
真正的刺突蛋白
疫苗RNA的下3777个字符类似于「密码子优化」,可以添加大量的C和G。
这里我们看到同义的RNA变化。例如,在第一个密码子中CUU变成了CUG。这给疫苗增加了另一个「G」,我们知道这有助于提高蛋白质的生产。
当我们比较疫苗中的整个刺突蛋白时,所有的变化都是同义的。除了两个,这就是我们在这里看到的。
上面的第三和第四个密码子代表了实际的变化。那里的K和V氨基酸都被P或脯氨酸所取代。对于「K」,这需要改变三次(「!!」),而对于「V」,这只需要改变两次(「!!」)。
事实证明,这两个变化极大地提高了疫苗的效率。
那么这里发生了什么?如果你看一个真正的冠状病毒粒子,你可以看到刺突蛋白:
这些刺钉被安装在病毒体内(「核衣壳蛋白」)。但问题是,我们的疫苗只会产生刺突,我们不会把它们植入任何一种病毒体内。
结果是,未经修饰的,独立的刺突蛋白崩溃成不同的结构。如果作为疫苗注射,这确实会使我们的身体产生免疫力。但只针对崩溃的刺突蛋白。
真正的冠状病毒是带着尖刺的。在这种情况下,疫苗不会很有效。
那么该怎么办呢?
2017年,有人描述了如何在正确的位置放置一个双脯氨酸替代,将使SARS-CoV-1和MERS S蛋白形成「预融合」结构,即使不是整个病毒的一部分。这是因为脯氨酸是一种非常坚硬的氨基酸。它就像一种夹板,在我们需要向免疫系统展示的状态下稳定蛋白质。
蛋白质的末端,下一步
如果我们浏览其余的源代码,我们会在刺突蛋白的末端遇到一些小的修改:
在蛋白质的末端,我们会发现一个「停止」密码子,在这里用小写的「s」表示。这是一种礼貌的说法,表示蛋白质应该到此为止。最初的病毒使用UAA终止密码子,疫苗使用两个UGA终止密码子,也许只是为了更好的措施。
3 'UTR
就像核糖体在5 '端需要引入,我们发现了' 5UTR,在蛋白质的末端我们发现了一个类似的结构,称为3 ' UTR。
关于3 ' UTR有很多说法,但这里引用维基百科的说法:「3 ' UTR在基因表达中起着至关重要的作用,它影响mRNA的定位、稳定性、输出和翻译效率。尽管我们目前对3 ' -UTRs有了解,但它们仍然是相对神秘的。」
我们所知道的是,某些3 ' UTR在促进蛋白质表达方面非常成功。根据世卫组织的文件,辉瑞疫苗3 ' UTR是从「split (AES) mRNA的氨基末端增强子和编码12S核糖体RNA的线粒体中提取的,以保证RNA的稳定性和高总蛋白表达」。
The AAAAAAAAAAAAAAAAAAAAAA end of it all
mRNA的最末端是聚腺苷化的。这是一种以「AAAAAAAAAAAAAAAAAAAAAA」的奇特结尾。
似乎,就连mRNA似乎也受够了这个糟糕的2020年!
mRNA可以重复使用很多次,但在这个过程中,它也会在末端失去一些A。一旦A耗尽,mRNA就不再起作用而被丢弃。这样,「多聚腺苷酸尾(Poly-A Tail)」就可以防止其退化。
有研究表明,对于mRNA疫苗来说,A的最佳数量是多少。我在公开文献中读到,这个数字在120左右达到了顶峰。
BNT162b2疫苗的是:
这是30个A,然后是「10个核苷酸连接体」(GCAUAUGACU),再后面是70个A。
太长不看版
如果上面的一切让你感到云里雾里,作者在这里为您准备了一份「太长不看版」:
帽子来确保RNA看起来像普通的mRNA
已知的成功和优化的5 ' UTR
密码子优化信号肽,将刺突蛋白送到正确的位置(100%从原始病毒复制)
原始刺的密码子优化版本,有两个「脯氨酸」替代,以确保蛋白质以正确的形式出现
一个已知的成功和优化的3 ' UTR
一个有点神秘的多聚腺苷酸尾(Poly-A Tail),里面有一个无法解释的「连接器」
密码子优化在mRNA上增加了大量的G和C。与此同时,用ψ(1-甲基-3 ' -伪尿酰ψ)而不是U来帮助逃避我们的免疫系统,因此mRNA会停留足够长的时间,所以我们实际上可以帮助训练免疫系统。
文章在reddit上引起了广泛讨论,学科间的边界似乎也越来越模糊。
一位网友看完后直言:我通过稍微修饰U核苷酸,可以使RNA越过我们的「安全系统」。我们的安全系真的糟透了!
你呢?你怎么看?
参考链接:
https://berthub.eu/articles/posts/reverse-engineering-source-code-of-the-biontech-pfizer-vaccine/
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