在抗原-抗体分子对接模拟所生成的大量计算生成构象中筛选出近天然结构,即接近真实情况的抗原-抗体结合模式。借鉴QSAR原理,定义抗原-抗体接触面描述符并利用Discovery Studio 4.5软件平台计算出各对接模拟构象的接触面描述符和能量参...在抗原-抗体分子对接模拟所生成的大量计算生成构象中筛选出近天然结构,即接近真实情况的抗原-抗体结合模式。借鉴QSAR原理,定义抗原-抗体接触面描述符并利用Discovery Studio 4.5软件平台计算出各对接模拟构象的接触面描述符和能量参数。构造训练集数据进行回归分析,建立预测对接模拟构象是否是近天然结构的数学模型。通过测试集和实际应用情况检验该数学模型。通过回归分析所建立的数学模型能够在成百上千的抗原-抗体对接模拟构象中有效筛选出其中的近天然结构,在测试集验证和4G7抗体结合模式预测应用中具有良好的表现,验证了该数学模型的有效性和实用性。经验性的抗原-抗体接触面特征如氢键密度、氨基酸对偏好性指数等以及能量参数能够共同有效表征近天然结构,所建立的数学模型有效增强了通过分子对接预测抗原-抗体结合模式的可行性。展开更多
PIK3R5 is the regulatory subunit of Phosphoinositide 3-kinase γ (PI3Kγ) that is responsible for phosphory-lating membrane lipids to activate the AKT pathway. PIK3R5 binds Gβγ and facilitates the interaction with p...PIK3R5 is the regulatory subunit of Phosphoinositide 3-kinase γ (PI3Kγ) that is responsible for phosphory-lating membrane lipids to activate the AKT pathway. PIK3R5 binds Gβγ and facilitates the interaction with p110γ catalytic subunit (PIK3CG) during PI3Kγ activation. The identification of PIK3R5 P629S mutation in AOA2 patients indicated a potential defect in the AKT pathway resulting from impaired PIK3R5 interaction with Gβγ and PIK3CG, defective AKT pathway can result in cerebellar cell death causing neurological symptoms. Our in silico macromolecular docking of the wild type and mutant PIK3R5 protein models with ligand revealed an energy requirement to maintain the mutant complexes compared to no energy required to maintain the wild type complexes, in addition, the mutant structures were loose compared to rigid wild type structures, such structural changes may impair the molecular function of the PIK3R5 and hence affect the AKT pathway.展开更多
Meanwhile the outbreak of the Covid-19 since December, 2019 in China, it has killed more than a hundred thousand of people of all ages and sex across the globe in a short span of time. On the bases of this study the n...Meanwhile the outbreak of the Covid-19 since December, 2019 in China, it has killed more than a hundred thousand of people of all ages and sex across the globe in a short span of time. On the bases of this study the nearest family member of the virus and its receptor binding domain of S protein including its model structure and function of its active sites were naked through Multiple Sequence Alignment, modelling and molecular docking software accordingly its repository genome databases. The virus was genetically associated and molecular evolutionary related with (<em>RaTG</em>13) and it scores 96.12% homology with 99% query coverage followed by <em>bat-SL-CoVZC</em>45 and<em> bat-SL-CoVZXC</em>21 notch 89.12% and 88.65% respectively. However, SARS and MERS corona type virus those outbreak earlier respectively less likely family members of 2019-nCoV. Though the virus has a close genetic association with those previous SARS coronaviruses, and certainly the spike protein used as a binding receptor to fight against human receptor protein of ACE 2, but on the basis of FRODOC and HDOCK server analysis multi favorable active sites of S protein was discovered such GLN493 shown as a finest key in both model and possessed a unique traits on it resulting unexpected rate of transmission and number of people died while compared to the previous one. TYR500, ASN501, GLN498 and others residues preferably contemplate site also. In particular, the diversity of the virus in the world may be due to the genome structure of the virus and S gene changed over the time, across the world against to host of human genetic diversity, which may be more robust, and may be a new and unique feature. This is because it is characterized close to contact with distance divergence between wild type novel coronavirus which was risen from China against to the genomes from Lebanon, India, Italy, and USA and so on. Thus, the World Health Organization and its researchers should focus on immunologic research and effective drug and vaccine development that展开更多
为探讨Bla g 2的E233A突变对抗原抗体相互作用的影响,从RCSB数据库下载德国小蠊致敏原Bla g 2野生型及其单克隆抗体4C3的NMR结构,运用Swiss PDB Viewer将Bla g 2野生型(E233-93Q)构建为突变型(E233A-93Q)三维结构;并将Bla g 2野生型和...为探讨Bla g 2的E233A突变对抗原抗体相互作用的影响,从RCSB数据库下载德国小蠊致敏原Bla g 2野生型及其单克隆抗体4C3的NMR结构,运用Swiss PDB Viewer将Bla g 2野生型(E233-93Q)构建为突变型(E233A-93Q)三维结构;并将Bla g 2野生型和突变型分别与其单克隆抗体4C3进行分子动力学模拟和蛋白-蛋白对接.结果表明:突变体E233A与单克隆抗体4C3结合能力下降,进而增加了与Ig E的结合力,可能加重过敏反应的发生.展开更多
The three-dimensional structure of a biomolecule rather than its one-dimensionM sequence determines its biological function. At present, the most accurate structures are derived from experimental data measured mainly ...The three-dimensional structure of a biomolecule rather than its one-dimensionM sequence determines its biological function. At present, the most accurate structures are derived from experimental data measured mainly by two techniques： X-ray crystallog- raphy and nuclear magnetic resonance （NMR） spec- troscopy. Because neither X-ray crystallography nor NMR spectroscopy could directly measure the positions of atoms in a biomolecule, algorithms must be designed to compute atom coordinates from the data. One salient feature of most NMR structure computation algorithms is their reliance on stochastic search to find the lowest energy conformations that satisfy the experimentally- derived geometric restraints. However, neither the cor- rectness of the stochastic search has been established nor the errors in the output structures could be quantified. Though there exist exact algorithms to compute struc- tures from angular restraints, similar algorithms that use distance restraints remain to be developed. An important application of structures is rational drug design where protein-ligand docking plays a crit- ical role. In fact, various docking programs that place a compound into the binding site of a target protein have been used routinely by medicinal chemists for both lead identification and optimization. Unfortunately, de- spite ongoing methodological advances and some success stories, the performance of current docking algorithms is still data-dependent. These algorithms formulate the docking problem as a match of two sets of feature points. Both the selection of feature points and the search for the best poses with the minimum scores are accomplished through some stochastic search methods. Both the un- certainty in the scoring function and the limited sam- pling space attained by the stochastic search contribute to their failures. Recently, we have developed two novel docking algorithms： a data-driven docking algorithm and a general docking algorithm that does not rely on experimental data. Our algorithms 展开更多
Molecular docking programs play a crucial role in drug design and development. In recent years, much attention has been devoted to the protein-peptide docking problem in which docking of a flexible peptide with a know...Molecular docking programs play a crucial role in drug design and development. In recent years, much attention has been devoted to the protein-peptide docking problem in which docking of a flexible peptide with a known protein is sought. In this work we present a new docking algorithm which is based on the use of a filling function method for continuos constrained global optimization. Indeed, the protein-peptide docking position is sought by minimizing the conformational potential energy subject to constraints necessary to maintain the primary sequence of the given peptide. The resulting global optimization problem is difficult mainly for two reasons. First, the problem is large scale in constrained global optimization;second, the energy function is multivariate non-convex so that it has many local minima. The method is based on the device of modifying the original objective function once a local minimum has been attained by adding to it a filling term. This allows the overall algorithm to escape from local minima thus, ultimately, giving the algorithm ability to explore large regions in the peptide conformational space. We present numerical results on a set of benchmark docking pairs and comparison with the well-known software package for molecular docking PacthDock.展开更多
OBJECTIVE Palythoa caribaeorum(class Anthozoa) is a zoanthid that together jellyfishes,hydra,and sea anemones,which are venomous and predatory,belongs to the Phyllum Cnidaria.The distinguished feature in these marine ...OBJECTIVE Palythoa caribaeorum(class Anthozoa) is a zoanthid that together jellyfishes,hydra,and sea anemones,which are venomous and predatory,belongs to the Phyllum Cnidaria.The distinguished feature in these marine animals is the cnidocytes in the body tissues,responsible for toxin production and injection that are used majorly for prey capture and defense.With exception for other anthozoans,the toxin cocktails of zoanthids have been scarcely studied and are poorly known.METHODS Based on the analysis of P.caribaeorum transcriptome,numerous predicted venom-featured polypeptides were identified,including allergens,neuro-toxins,membrane-active and Kunitz-like peptides(PcKuz).The three predicted PcKuz isotoxins(1 to 3) were selected for functional studies.Through computational processing comprising structural phylogenetic analysis,molecular docking,and dynamics simulation,PcKuz3 was shown to be a potential voltage gated potassium-channel inhibitor.RESULTS PcKuz3 fitted well as new functional Kunitz-type toxins with strong anti-locomotor activity as in vivo assessed in zebrafish larvae,with weak inhibitory effect toward proteases,as evaluated in vitro.Notably,PcKuz3 can suppress,at low concentration,the 6-OHDA-induced neurotoxicity on the locomotive behavior of zebrafish,which indicated PcKuz3 may have a neuroprotective effect.CONCLUSION Taken together,PcK uz3 figures as a novel neurotoxin structure which differs from known homologous peptides expressed in sea anemone.Moreover,the novel PcKuz3 provides an insightful hint for bio-drug development for prospective neurodegenerative disease treatment.展开更多
文摘在抗原-抗体分子对接模拟所生成的大量计算生成构象中筛选出近天然结构,即接近真实情况的抗原-抗体结合模式。借鉴QSAR原理,定义抗原-抗体接触面描述符并利用Discovery Studio 4.5软件平台计算出各对接模拟构象的接触面描述符和能量参数。构造训练集数据进行回归分析,建立预测对接模拟构象是否是近天然结构的数学模型。通过测试集和实际应用情况检验该数学模型。通过回归分析所建立的数学模型能够在成百上千的抗原-抗体对接模拟构象中有效筛选出其中的近天然结构,在测试集验证和4G7抗体结合模式预测应用中具有良好的表现,验证了该数学模型的有效性和实用性。经验性的抗原-抗体接触面特征如氢键密度、氨基酸对偏好性指数等以及能量参数能够共同有效表征近天然结构,所建立的数学模型有效增强了通过分子对接预测抗原-抗体结合模式的可行性。
文摘PIK3R5 is the regulatory subunit of Phosphoinositide 3-kinase γ (PI3Kγ) that is responsible for phosphory-lating membrane lipids to activate the AKT pathway. PIK3R5 binds Gβγ and facilitates the interaction with p110γ catalytic subunit (PIK3CG) during PI3Kγ activation. The identification of PIK3R5 P629S mutation in AOA2 patients indicated a potential defect in the AKT pathway resulting from impaired PIK3R5 interaction with Gβγ and PIK3CG, defective AKT pathway can result in cerebellar cell death causing neurological symptoms. Our in silico macromolecular docking of the wild type and mutant PIK3R5 protein models with ligand revealed an energy requirement to maintain the mutant complexes compared to no energy required to maintain the wild type complexes, in addition, the mutant structures were loose compared to rigid wild type structures, such structural changes may impair the molecular function of the PIK3R5 and hence affect the AKT pathway.
文摘Meanwhile the outbreak of the Covid-19 since December, 2019 in China, it has killed more than a hundred thousand of people of all ages and sex across the globe in a short span of time. On the bases of this study the nearest family member of the virus and its receptor binding domain of S protein including its model structure and function of its active sites were naked through Multiple Sequence Alignment, modelling and molecular docking software accordingly its repository genome databases. The virus was genetically associated and molecular evolutionary related with (<em>RaTG</em>13) and it scores 96.12% homology with 99% query coverage followed by <em>bat-SL-CoVZC</em>45 and<em> bat-SL-CoVZXC</em>21 notch 89.12% and 88.65% respectively. However, SARS and MERS corona type virus those outbreak earlier respectively less likely family members of 2019-nCoV. Though the virus has a close genetic association with those previous SARS coronaviruses, and certainly the spike protein used as a binding receptor to fight against human receptor protein of ACE 2, but on the basis of FRODOC and HDOCK server analysis multi favorable active sites of S protein was discovered such GLN493 shown as a finest key in both model and possessed a unique traits on it resulting unexpected rate of transmission and number of people died while compared to the previous one. TYR500, ASN501, GLN498 and others residues preferably contemplate site also. In particular, the diversity of the virus in the world may be due to the genome structure of the virus and S gene changed over the time, across the world against to host of human genetic diversity, which may be more robust, and may be a new and unique feature. This is because it is characterized close to contact with distance divergence between wild type novel coronavirus which was risen from China against to the genomes from Lebanon, India, Italy, and USA and so on. Thus, the World Health Organization and its researchers should focus on immunologic research and effective drug and vaccine development that
文摘为探讨Bla g 2的E233A突变对抗原抗体相互作用的影响,从RCSB数据库下载德国小蠊致敏原Bla g 2野生型及其单克隆抗体4C3的NMR结构,运用Swiss PDB Viewer将Bla g 2野生型(E233-93Q)构建为突变型(E233A-93Q)三维结构;并将Bla g 2野生型和突变型分别与其单克隆抗体4C3进行分子动力学模拟和蛋白-蛋白对接.结果表明:突变体E233A与单克隆抗体4C3结合能力下降,进而增加了与Ig E的结合力,可能加重过敏反应的发生.
文摘The three-dimensional structure of a biomolecule rather than its one-dimensionM sequence determines its biological function. At present, the most accurate structures are derived from experimental data measured mainly by two techniques： X-ray crystallog- raphy and nuclear magnetic resonance （NMR） spec- troscopy. Because neither X-ray crystallography nor NMR spectroscopy could directly measure the positions of atoms in a biomolecule, algorithms must be designed to compute atom coordinates from the data. One salient feature of most NMR structure computation algorithms is their reliance on stochastic search to find the lowest energy conformations that satisfy the experimentally- derived geometric restraints. However, neither the cor- rectness of the stochastic search has been established nor the errors in the output structures could be quantified. Though there exist exact algorithms to compute struc- tures from angular restraints, similar algorithms that use distance restraints remain to be developed. An important application of structures is rational drug design where protein-ligand docking plays a crit- ical role. In fact, various docking programs that place a compound into the binding site of a target protein have been used routinely by medicinal chemists for both lead identification and optimization. Unfortunately, de- spite ongoing methodological advances and some success stories, the performance of current docking algorithms is still data-dependent. These algorithms formulate the docking problem as a match of two sets of feature points. Both the selection of feature points and the search for the best poses with the minimum scores are accomplished through some stochastic search methods. Both the un- certainty in the scoring function and the limited sam- pling space attained by the stochastic search contribute to their failures. Recently, we have developed two novel docking algorithms： a data-driven docking algorithm and a general docking algorithm that does not rely on experimental data. Our algorithms
文摘Molecular docking programs play a crucial role in drug design and development. In recent years, much attention has been devoted to the protein-peptide docking problem in which docking of a flexible peptide with a known protein is sought. In this work we present a new docking algorithm which is based on the use of a filling function method for continuos constrained global optimization. Indeed, the protein-peptide docking position is sought by minimizing the conformational potential energy subject to constraints necessary to maintain the primary sequence of the given peptide. The resulting global optimization problem is difficult mainly for two reasons. First, the problem is large scale in constrained global optimization;second, the energy function is multivariate non-convex so that it has many local minima. The method is based on the device of modifying the original objective function once a local minimum has been attained by adding to it a filling term. This allows the overall algorithm to escape from local minima thus, ultimately, giving the algorithm ability to explore large regions in the peptide conformational space. We present numerical results on a set of benchmark docking pairs and comparison with the well-known software package for molecular docking PacthDock.
基金Macao Science and Technology Development Fund (017/2015/AMJ134/2014/A3).
文摘OBJECTIVE Palythoa caribaeorum(class Anthozoa) is a zoanthid that together jellyfishes,hydra,and sea anemones,which are venomous and predatory,belongs to the Phyllum Cnidaria.The distinguished feature in these marine animals is the cnidocytes in the body tissues,responsible for toxin production and injection that are used majorly for prey capture and defense.With exception for other anthozoans,the toxin cocktails of zoanthids have been scarcely studied and are poorly known.METHODS Based on the analysis of P.caribaeorum transcriptome,numerous predicted venom-featured polypeptides were identified,including allergens,neuro-toxins,membrane-active and Kunitz-like peptides(PcKuz).The three predicted PcKuz isotoxins(1 to 3) were selected for functional studies.Through computational processing comprising structural phylogenetic analysis,molecular docking,and dynamics simulation,PcKuz3 was shown to be a potential voltage gated potassium-channel inhibitor.RESULTS PcKuz3 fitted well as new functional Kunitz-type toxins with strong anti-locomotor activity as in vivo assessed in zebrafish larvae,with weak inhibitory effect toward proteases,as evaluated in vitro.Notably,PcKuz3 can suppress,at low concentration,the 6-OHDA-induced neurotoxicity on the locomotive behavior of zebrafish,which indicated PcKuz3 may have a neuroprotective effect.CONCLUSION Taken together,PcK uz3 figures as a novel neurotoxin structure which differs from known homologous peptides expressed in sea anemone.Moreover,the novel PcKuz3 provides an insightful hint for bio-drug development for prospective neurodegenerative disease treatment.
