《自然—通讯》:科学家在蛋白质设计领域取得进展

近日,中国科学技术大学生命科学学院刘海燕教授、陈泉副教授研究组在蛋白质设计领域取得重要进展,成功实现给定目标结构的蛋白全序列从头设计。研究成果近日发表在《自然—通讯》杂志上。蛋白质是生命功能的主要执行者,是由不同类型的氨基酸按照特定顺序串联成的长链状生物大分子。刘海燕和陈泉研究组建立了一种用全新策略构建的统计能量函数,用于蛋白质设计。理论分析表明,其设计结果显著不同,且在一些重要方面优于现有最好的蛋白质设计模型。     

幽门螺旋菌的蛋白互作图谱

蛋白－蛋白相互作用是决定蛋白质功能的关键因素,因此科学家们对利用基因组序列建立蛋白质作用图谱很感兴趣。Nature 杂志409卷 6817期第211页（ 2001年1月11日出版）报道了人类胃脏病原体幽门螺旋菌的一个蛋白－蛋白相互作用图谱。这一新的互作图谱是以域、而不是以整体蛋白质的相互作用为基础的。它反映了1200多种潜在的蛋白质相互作用,涉及半数蛋白组由其基因组表达的全部蛋白成员。这类图件的用途是,建立用于在设计药物时分析修复失常过程可能性的方法。幽门螺旋菌的蛋白互作图谱@孙雷心     

应用自然界的规律与化学家的工具是创造新蛋白质的一条途径

最近蛋白质研究的一个新领域引起了人们的关注,它被雄心勃勃地称为‘从头设计蛋白质’。M.Mutter认为,设计予定立体构象的多肽顺序的工作由于对蛋白质折迭与拓扑结构的规律认识有限而受到阻碍。将化学合成的非天然的链用于构建蛋白质可以克服从头合成(de novo design)蛋白质时遇到的这种困难。     

药效假说在配体从头设计中的适用性探讨

在基于靶蛋白结构的多肽分子设计中,药效假说是从头设计方法的基本前提。虽然该假说是否成立已有不少议论,但尚未见到系统分析的报道。通过对８个蛋白质复物界面做了氨基酸模拟图谱,并从模拟图谱的结构偏差与能量分量的关系,对药效假说的适用条件进行了讨论。同时也给出一个ＨＩＶ－１蛋白酶及抑制剂复合物的功能图谱。从所得结果来看,药效假说在以氨基酸为药效基团时,尽管不少情况下仍然有效,但不是谱遍成立的。     

药效假说在配体从头设计中的适用性探讨

在基于靶蛋白结构的多肽分子设计中,药效假说是从头设计方法的基本前提。虽然该假说是否成立已有不少议论,但尚未见到系统分析的报道。通过对８ 个蛋白质复合物界面做了氨基酸模拟图谱,并从模拟图谱的结构偏差与能量分量的关系,对药效假说的适用条件进行了讨论。同时也给出一个ＨＩＶ－ １ 蛋白酶及抑制剂复合物的功能图谱。从所得结果来看,药效假说在以氨基酸为药效基团时,尽管不少情况下仍然有效,但不是普遍成立的。     

蛋白质工程：从定向进化到计算设计

定向进化通过建立突变体文库与高通量筛选方法,快速提升蛋白的特定性质,是目前蛋白质工程最为常用的蛋白质设计改造策略。近十年随着计算机运算能力大幅提升以及先进算法不断涌现,计算机辅助蛋白质设计改造得到了极大的重视和发展,成为蛋白质工程新开辟的重要方向。以结构模拟与能量计算为基础的蛋白质计算设计不但能改造酶的底物特异性与热稳定性,还可从头设计具有特定功能的人工酶。近年来机器学习等人工智能技术也被应用于计算机辅助蛋白质设计改造,并取得瞩目的成绩。文中介绍了蛋白质工程的发展历程,重点评述当前计算机辅助蛋白质设计改造方面的进展与应用,并展望其未来发展方向。     

蛋白质结构从头预测方法研究进展

蛋白质结构从头预测是不依赖模板仅从氨基酸序列信息得到天然结构。它的关键是正确定义能量函数、精确选用计算机搜索算法来寻找能量最低值。基于此,本文系统介绍了能量函数和构象搜索策略,并列举了几种比较成功的从头预测方法,通过比较得出结论:基于统计学知识的能量函数是近年来从头预测发展的主要方向,现有从头预测的构象搜索都用到Monte Carlo法。这表明随着蛋白质结构预测研究的深入,能量函数的构建、构象搜索方法的选择、大分子蛋白质结构的从头预测等关键性问题都取得了突破性进展。     

蛋白质组研究中肽质量指纹谱鉴定方法的建立及应用

建立了用肽质量指纹谱和数据库检索方法鉴定凝胶电泳分离蛋白南的方法。用标准蛋白质对胶上蛋白５质原位酶切制备肽谱的方法进行了讨论。分析了实际细胞蛋白质样品,获得双向电泳分离的人肺癌细胞蛋白质谱中三个蛋白质点的肽指纹谱。并通过数据７库检索分别鉴定为甘油醛－３－磷酸脱氢酶－２,测在蛋白羟基末端水解同工酶和丙糖磷酸异构酶。     

神经末梢突触囊泡释放神经递质过程的调控蛋白

神经末梢突触囊泡释放神经递质是一个复杂且受到精细调控的过程,涉及多种蛋白质间的相互作用。位于突触囊泡膜上的突触囊泡蛋白／突触囊泡相关膜蛋白（synaptobrevin/VAMP),与位于突触前膜上的syntaxin和突触小体相关蛋白SNAP－25,三者聚合形成的可溶性N－甲基马来酰胺敏感因子（NSF）附着蛋白受体（SNARE）核心复合物是突触囊泡胞吐过程中的核心成分。本文主要围绕参与空触囊泡胞吐过程,以及调节SNARE核心复合物的形成,解离及其功能的蛋白质,并对突触囊泡胞吐过程的分子模型作一概述。     

环化腺苷酸和蛋白激酶的结合部位——从头计算法的研究

本文应用从头计算法和CNDO法对cAMP分子进行了计算,讨论了它的电子结构特点和蛋白质(依赖cAMP的蛋白激酶和cAMP受体蛋白)的相互作用.     

A Unique Protease Cleavage Site Predicted in the Spike Protein of the Novel Pneumonia Coronavirus (2019-nCoV) Potentially Related to Viral Transmissibility

正Dear Editor,In December 2019, a novel human coronavirus caused an epidemic of severe pneumonia(Coronavirus Disease 2019,COVID-19) in Wuhan, Hubei, China(Wu et al. 2020; Zhu et al. 2020). So far, this virus has spread to all areas of China and even to other countries. The epidemic has caused 67,102 confirmed infections with 1526 fatal cases     

Curcuminoids as inhibitors of thioredoxin reductase: A receptor based pharmacophore study with distance mapping of the active site

Curcumin is the yellow pigment of turmeric that interacts irreversibly forming an adduct with thioredoxin reductase (TrxR), an enzyme responsible for redox control of cell and defence against oxidative stress. Docking at both the active sites of TrxR was performed to compare the potency of three naturally occurring curcuminoids, namely curcumin, demethoxy curcumin and bis-demethoxy curcumin. Results show that active sites of TrxR occur at the junction of E and F chains. Volume and area of both cavities is predicted. It has been concluded by distance mapping of the most active conformations that Se atom of catalytic residue SeCYS498, is at a distance of 3.56 from C13 of demethoxy curcumin at the E chain active site, whereas C13 carbon atom forms adduct with Se atom of SeCys 498. We report that at least one methoxy group in curcuminoids is necessary for interation with catalytic residues of thioredoxin. Pharmacophore of both active sites of the TrxR receptor for curcumin and demethoxy curcumin molecules has been drawn and proposed for design and synthesis of most probable potent antiproliferative synthetic drugs.     

Comparative morphology of the carpel in the Liliaceae: Hewardieae, Petrosavieae, and Tricyrteae

The young pistils in the melanthioid tribes, Hewardieae, Petrosavieae and Tricyrteae, are uniformly tricarpellate and syncarpous. They lack raphide idioblasts. All are multiovulate, with bitegmic ovules. The Petrosavieae are marked by the presence of septal glands and incomplete syncarpy. Tepals and stamens adhere to the ovary in the Hewardieae and the Petrosavieae but not in the Tricyrteae. Two vascular bundles occur in the stamens of the Hewartlieae and Tricyrtis latifolia. Ventral bundles in the upper part of the ovary of the Hewardieae are continuous with compound septal bundles and placental bundles in the lower part. Putative ventral bundles occur in the alternate position in the Tricyrteae and putative placental bundles in the opposite. position in the Petrosavieae. The dichtomously branched stigma in each carpel of the Tricyrteae is supplied by a bifurcated dorsal bundle.     

Enterovirus 71 3C proteolytically processes the histone H3 N-terminal tail during infection

Highlights
1. The N-terminal tail of histone H3 is specifically cleaved during EV71 infection.
2. Viral protease 3C is identified as a protease responsible for proteolytically processing the N-terminal H3 tail.
3. Our finding reveals a new epigenetic regulatory mechanism for Enterovirus 71 in virus-host interactions.     

Detection of EBV and HHV6 in the Brain Tissue of Patients with Rasmussen’s Encephalitis

Rasmussen’s encephalitis (RE) is a rare pediatric neurological disorder, and the exact etiology is not clear. Viral infection may be involved in the pathogenesis of RE, but conflicting results have reported. In this study, we evaluated the expression of both Epstein-Barr virus (EBV) and human herpes virus (HHV) 6 antigens in brain sections from 30 patients with RE and 16 control individuals by immunohistochemistry. In the RE group, EBV and HHV6 antigens were detected in 56.7% (17/30) and 50% (15/30) of individuals, respectively. In contrast, no detectable EBV and HHV6 antigen expression was found in brain tissues of the control group. The co-expression of EBV and HHV6 was detected in 20.0% (6/30) of individuals. In particular, a 4-year-old boy had a typical clinical course, including a medical history of viral encephalitis, intractable epilepsy, and hemispheric atrophy. The co-expression of EBV and HHV6 was detected in neurons and astrocytes in the brain tissue, accompanied by a high frequency of CD8⁺ T cells. Our results suggest that EBV and HHV6 infection and the activation of CD8⁺ T cells are involved in the pathogenesis of RE.     

Perinatal Vertical Transmission of Chikungunya Virus in Ruili,a Town on the Border between China and Myanmar

正Dear Editor,Chikungunya virus (CHIKV), an arbovirus in the family of Togaviridae, genus Alphavirus, is transmitted by the A.aegyptii or A. albopictus mosquito, and causes disease in humans characterized by fever, rash, and arthralgia (Silva and Dermody 2017; Suhrbier 2019). It was first reported in 1953 in Tanzania, and caused only a few outbreaks and sporadic cases in Africa and Asia in last century. However, in the epidemic in 2004, CHIKV acquired mutations that conferred enhanced transmission by the A. albopictus mosquito(Schuffenecker et al. 2006). Since then, it has successively caused outbreaks in Africa, the Indian Ocean, South East Asia, the South America, and Europe (Zeller et al. 2016).     

Development of a Novel Reverse Transcription Loop-Mediated Isothermal Amplification Method for Rapid Detection of SARS-CoV-2

In conclusion, the novel visual RT-LAMP assay is a simple, rapid, and sensitive approach for detection of SARS-CoV-2, and it is ready for application in primary care and community hospitals or health care centers, and even patients' own houses in response to the current SARS-CoV-2 epidemic because the assay does not require sophisticated equipment and skilled personnel. Furthermore, it is also ready to be used in fields for screening samples from wild animals and environments to facilitate the identification of potential intermediate hosts that mediate the cross-species transmission of SARS-CoV-2 from bats to humans.