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相关概念视频

Pinching-off of Coated Vesicles01:32

Pinching-off of Coated Vesicles

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Vesicle budding is orchestrated by distinct cytosolic proteins such as adaptor proteins, coat proteins, and GTPases. To initiate vesicle budding, membrane-bending proteins containing crescent-shaped BAR domains bind to the lipid heads in the bilayer and distort the membrane to form a protein-coated vesicle bud. Adaptors proteins such as AP2 for clathrin-coated vesicles can nucleate on the deformed membrane. Finally, coat proteins such as clathrin or COPI and COPII assemble into a coat forming...
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Noncovalent Attractions in Biomolecules02:35

Noncovalent Attractions in Biomolecules

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Noncovalent attractions are associations within and between molecules that influence the shape and structural stability of complexes. These interactions differ from covalent bonding in that they do not involve sharing of electrons.
Four types of noncovalent interactions are hydrogen bonds, van der Waals forces, ionic bonds, and hydrophobic interactions.
Hydrogen bonding results from the electrostatic attraction of a hydrogen atom covalently bonded to a strong-electronegative atom like oxygen,...
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Clathrin Coated Vesicles01:12

Clathrin Coated Vesicles

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Clathrin-coated vesicles use endocytosis to transport receptors and lysosomal hydrolases from the Golgi to the lysosome in the late secretory pathway. Clathrin-mediated endocytosis was the first described endocytic process, and Clathrin-coated vesicles remain one of the most well-studied transport vesicles. The molecular machinery that generates clathrin-coated vesicles comprises over 50 proteins that precisely coordinate vesicle formation. Cell surface receptors concentrated in indented sites...
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COP Coated Vesicles00:59

COP Coated Vesicles

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Membrane-enclosed structures called vesicles transport proteins and lipids across the cell. The vesicles derive their cargo from the plasma membrane, Golgi, ER, or endosome. Coated vesicles are spherical, protein-coated carriers with a 50–100 nm diameter that mediate bidirectional transport between the ER and the Golgi. The distribution of proteins between the ER and Golgi complex is dynamic and is maintained by different coated vesicles. Their formation is driven by the assembly of...
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Assembly of Signaling Complexes01:30

Assembly of Signaling Complexes

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Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
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Coat Assembly and GTPases01:33

Coat Assembly and GTPases

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Vesicles incorporate different coat protein subunits in different cell locations, which changes the properties of the coat, such as the shape and geometry of the transport vesicles. Thus, vesicle coat proteins also play a significant role in cargo selection.
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相关实验视频

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Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
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Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis

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两步共价对接与吸引腔的对接

Mathilde Goullieux1, Vincent Zoete1,2, Ute F Röhrig1

  • 1SIB Swiss Institute of Bioinformatics, Molecular Modeling Group, CH-1015 Lausanne, Switzerland.

Journal of chemical information and modeling
|December 4, 2023
PubMed
概括

一个新的共价对接程序,吸引腔 (AC),准确地预测药物相互作用. 在模拟共价药物结合机制方面,AC优于GOLD和AutoDock等现有方法.

科学领域:

  • 计算化学是一种计算化学.
  • 药物发现 药物发现
  • 结构生物学是结构生物学.

背景情况:

  • 联药物提供了优势,增加了对其开发的兴趣.
  • 准确预测药物向相互作用对于计算机辅助药物设计至关重要.
  • 现有的对接算法需要对共价联体结合进行改进.

研究的目的:

  • 开发和验证一个新的共价对接程序,用于吸引空隙 (AC) 代码.
  • 为了模仿共价联结体的两步结合机制.
  • 为了评估AC的性能与既有对接工具对比.

主要方法:

  • 开发了AC代码的共价对接程序,模拟非结合的相互作用,随后形成共价键.
  • 为重新对接和交叉对接的验证创建了304共价复合体的基准集.
  • 将AC的成功率与GOLD和AutoDock进行比较,使用RMSD标准≤2 Å和≤1.5 Å.

主要成果:

  • 在基准测试中,AC的成功率为78% (RMSD ≤ 2 Å),超过了GOLD (66%) 和AutoDock (35%).
  • 使用更严格的标准 (RMSD ≤ 1.5 Å),AC获得了71%的成功率,而GOLD的成功率为55%,AD的26%.
  • 在SARS-CoV-2主要蛋白酶复合体上,AC显示58%的重新对接和28%的交叉对接成功率.

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结论:

  • 交流共价对接程序准确地模拟了共价连接体结合.
  • 与GOLD和AutoDock相比,AC在共价对接方面表现出优越的性能.
  • 这种方法是推进共价抑制剂计算机辅助药物设计的宝贵工具.