Peptide reagent design based on physical and chemical properties of amino acid residues

It has tremendous values for both drug discovery and basic research to develop a solid bioinformatical tool for guiding peptide reagent design. Based on the physical and chemical properties of amino acids, a new strategy for peptide reagent design, the so-called AABPD (amino acid based-peptide design), is proposed. The peptide samples in a training dataset are described by a series of HMLP (heuristic molecular lipophilicity potential) parameters and other physicochemical properties of amino acid residues that form a three-dimensional data matrix where each component is defined by three indexes: the first index refers to the peptide samples, the second to the amino acid positions, and the third to the amino acid parameters. The binding free energy between a peptide ligand and its protein receptor is calculated by a linear free energy equation through the physicochemical parameters, resulting in a set of simultaneous linear equations between the bioactivity of the peptides and the physicochemical properties of amino acids. An iterative double least square technique is developed for the solution of the three-dimensional simultaneous linear equation set to determine the amino acid position coefficients of peptide sequence and the physicochemical parameter coefficients of amino acid residues alternately. The two sets of coefficients thus obtained are used for predicting the bioactivity of other query peptide reagents. Two calculation examples, the peptide substrate specificity of the SARS coronavirus 3C-like proteinase and the affinity prediction for epitope-peptides with Class I MHC molecules are studied by using the peptide reagent design strategy.     

Computational characterization and design of SARS coronavirus receptor recognition and antibody neutralization

The sequential determination of crystal structures of the SARS coronavirus spike receptor-binding domain (RBD) in complex with its cellular receptor or neutralizing antibody opened a door for the design and development of antiviral competitive inhibitors. Based on those complex structures, we conduct computational characterization and design of RBD-mediated receptor recognition and antibody neutralization. The comparisons between computational predictions and experimental evidences validate our structural bioinformatics protocols. And the calculations predict a number of single substitutions on RBD, receptor or antibody that could remarkably elevate the binding affinities of those complexes. It is reasonable to anticipate our structure-based computation-derived hypotheses could be informative to the future biochemical and immunological tests.     

Estimation of the number of failures in the Weibull model using the ordinary differential equation

In estimating the number of failures using right truncated grouped data, we often encounter cases that the estimate is smaller than the true one when we use the likelihood principle to conditional probability. In infectious disease spread predictions, the SIR model described by simultaneous ordinary differential equations is commonly used, and it can predict reasonably well the number of infected patients even when the size of observed data is small. We have investigated whether the ordinary differential equation model can estimate the number of failures more accurately than does the likelihood principle under the condition of right truncated grouped data. The positive results are obtained in the Weibull model, similarly to the cases of the SARS, A(H1N1), and FMD.     

呼肠病毒与细胞凋亡

从SARS患者生前咽拭子和尸检肺组织分离病毒阳性的培养细胞超薄切片中,在电子显微镜下不仅发现了呼肠病毒,而且还查见具有超微结构形态特征的凋亡细胞。凋亡早期的感染细胞,其细胞核染色质浓缩、边集显著,胞浆内尚可查见病毒包涵体的残迹。多数凋亡细胞胞浆内未查见呼肠病毒及其包涵体。在早期,凋亡细胞胞核形状变化不大,核染色质呈不规则的边集、浓缩,或呈平台状。继而,凋亡细胞胞核形状高度不规则,染色质浓缩、致密,可见核孔残迹,但细胞轮廓尚保存完好,外周可查见含核质凋亡小体。到后期,凋亡细胞高度皱缩．核固缩并碎裂成细小的片块或颗粒,胞质稀少,胞体呈芽球状,细胞膜外围可查见大小不等、形状多样的含核质凋亡小体。此研究结果提示：与SARS相关呼肠病毒所诱导的细胞凋亡有可能在SARS的发病机制中起重要作用。     

SARS冠状病毒主要蛋白酶二聚体静电和疏水效应的研究

从三种冠状病毒主要蛋白酶SARS 3CL, HCoV 3CL和TGEC 3CL蛋白酶结构出发,着重研究了三种蛋白酶二聚体单体之间的静电和疏水相互作用.用连续介质模型有限差分方法计算得到三种蛋白二聚体界面处的静电势,发现三种蛋白酶单体和单体之间静电势分布具有明显的互补性,三种蛋白酶二聚体单体之间具有相同的静电相互作用能.用溶剂可及表面积模型分析了分子表面积及疏水性,发现三种蛋白酶具有相同的疏水分布,其中SARS 3CL蛋白酶疏水率为74%,驱动其单体聚合成二聚体.对三种蛋白酶的去溶剂化能疏水项的计算表明,三种蛋白酶二聚体单体之间具有相似的疏水相互作用能.     

SARS病毒E蛋白的计算机模拟的初步研究

以粗粒化的多肽链模型进行了SARS病毒包膜中E蛋白的计算机模拟,描述了该蛋白质空间构象的概貌.首先扩展了多肽链的HP模型,使之能够用于研究在水或脂环境下蛋白质折叠的行为,并且考虑了全部氨基酸残基疏水相互作用能的差异.相关格子链的MonteCarlo模拟显示了很高的计算效率.模拟再现了蛋白质的coil-globule转变,验证了蛋白质序列分布的重要性.结果表明,在水环境中,E蛋白质空间结构由紧致的疏水内核和部分向外延伸的亲水片段组成;在脂环境中,中部疏水片段会成为向外延伸的环,而当两侧紧致的亲水片段分开时,则形成桥.     

Analysis on stability of an autonomous dynamics system for sars epidemic

Introduction Severeacuterespiratorysyndrome(SARS)spreadsmostrapidlythroughthe23areasand countriesintheworldsincethefirstSARScasewasreportedinGuangdonginNovember,2002andreachedtheitsclimaxinApril May2003.Althoughtheperiodoftheepidemicwasover now,itwasnotclearaboutSARSorigin,themechanismoftransmission,andtheregularityof SARSemergingexceptthatSARSasanovelcoronaviruswasknown.ThestudiesofSARS weremadebyavarietyofwaysandinmanyfieldsinorderthatSARSwouldbewellknown andeffectivemeasuresofi…     

一类SARS传染病自治动力系统的稳定性分析

在K-M传染病模型的基础上,进一步考虑易感人群的密度制约以及患病者类的死亡与治愈率等因素,建立了描述SARS传染病的一个新的动力学模型,分析了该模型平衡点的稳定性态．证明了疾病消除平衡点在一定条件下是全局渐进稳定的,而地方病平衡点不是渐近稳定的．得到了该传染病系统在适当条件下为永久持续生存的结果．     

静电和疏水效应对SARS冠状病毒3CL蛋白酶二聚体稳定性的影响

从TGEV3CL蛋白酶二聚体结构出发,研究了TGEV3CL蛋白酶二聚体单体之间的静电和疏水相互作用.蛋白质的静电相互作用通过有限差分方法求解Poisson-Boltzmann方程得到,疏水相互作用通过分析溶剂可及性表面模型得到.考察了不同pH值对SARS3CL蛋白酶二聚体静电和疏水相互作用的影响,在pH=5.5～8.5时,二聚体静电相互作用能、静电去溶剂化能和疏水自由能都具有较小的数值,表明在该条件下静电和疏水相互作用有利于二聚体的稳定存在.由于SARS3CL蛋白酶活性模式为二聚体,因此,在该pH值范围内,有利于蛋白酶保持活性.在pH=7.0条件下,蛋白酶单体之间具有最强的静电和疏水相互作用,从而使蛋白酶具有最强的活性,这与实验结果相一致.pH值对静电去溶剂化能的影响大于疏水自由能,表明静电作用是造成强酸或强碱条件下二聚体不能稳定存在的主要原因.     

关于SARS病毒传播的马尔可夫骨架过程模型

根据SARS病毒传播的特性和侯振挺等人提出的马尔可夫骨架过程理论，建立了SARS病毒传播的马尔可夫骨架模型，并得出结论，在任一时刻的疑似病例数，传染病人数是某非负线性方程组的最小非负解。