Theoretical Studies of Protein-Ligand Binding Energetics and Kinetics

蛋白质-配体结合能量学和动力学的理论研究

基本信息

  • 批准号:
    9808202
  • 负责人:
  • 金额:
    $ 28.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
    Continuing grant
  • 财政年份:
    1998
  • 资助国家:
    美国
  • 起止时间:
    1998-10-01 至 2003-09-30
  • 项目状态:
    已结题

项目摘要

9808202 Sharp This research is directed at understanding the physical and chemical basis of specific binding of proteins to their ligands. The goal is to answer two key questions that play an important part in the biological function of proteins: i) How do the structure and chemical properties of the protein and ligand result in favorable energetics (high affinity) for the correct binding complex? ii) How do the structure and chemical properties control the dissociation kinetics under applied forces. The binding free energy will be calculated using a combination of molecular mechanics and finite difference Poisson-Boltzmann methods. Changes in internal translation and ratational entropy in the complex will be computed from fluctuations in the structure obtained from molecular dynamics simulations. Brownian dynamics will be used to study the dissociation kinetics of protein-ligand systems in the presence of intrinsic and extrinsic (mechanical) forces. Solvent screened forces that affect the dissociation will be included using a finite difference Poisson-Boltzmann approach. Brownian dynamics simulations will be used to understand the relationship between structure and dissociation kinetics of protein-ligand interactions that do or do not mediate cell adhesion. The ability to calculate and eventually predict how tightly a protein binds other molecules (ligand) may be termed the "binding affinity problem", and it ranks in importance with other major problems in modern structural biology such as the "protein folding problem", and the basis of catalytic activity in proteins. The ability to understand how the structure of a protein enables it to bind a specific target molecule will increase our understanding of many biological events at the molecular level such as antibody-antigen-affinity, antigenicity, specificity in signal transduction pathways, the function of inhibitors, etc. Applications of research on the binding problem also include protein engineering. Understanding the mechanism an d rate at which proteins become unbound from their ligands in the presence of forces is important in understanding the different adhesion behaviors shown by cells. The ability to simulate dissociation kinetics will shed light on the relationship between molecular structure, dissociation and biologically important functions such as cell adhesion.
9808202 Sharp本研究旨在了解蛋白质与其配体特异性结合的物理和化学基础。 目标是回答在蛋白质的生物学功能中起重要作用的两个关键问题:i)蛋白质和配体的结构和化学性质如何导致正确结合复合物的有利能量(高亲和力)?ii)结构和化学性质如何控制施加力下的解离动力学。 结合自由能将使用分子力学和有限差分Poisson-Boltzmann方法的组合来计算。在复杂的内部翻译和旋转熵的变化将计算从分子动力学模拟获得的结构的波动。 布朗动力学将用于研究蛋白质-配体系统在内在和外在(机械)力存在下的解离动力学。 将使用有限差分Poisson-Boltzmann方法包括影响解离的溶剂屏蔽力。 布朗动力学模拟将被用来了解蛋白质-配体相互作用的结构和解离动力学之间的关系,做或不介导细胞粘附。 计算并最终预测蛋白质与其他分子(配体)结合的紧密程度的能力可以被称为“结合亲和力问题”,它与现代结构生物学中的其他主要问题(如“蛋白质折叠问题”)以及蛋白质催化活性的基础同等重要。了解蛋白质的结构如何使其能够结合特定的靶分子的能力将增加我们在分子水平上对许多生物学事件的理解,例如抗体-抗原-亲和力、抗原性、信号转导途径中的特异性、抑制剂的功能等。 了解蛋白质在力的作用下与其配体结合的机制和速率对于理解细胞表现出的不同粘附行为是重要的。 模拟解离动力学的能力将揭示分子结构,解离和生物学重要功能,如细胞粘附之间的关系。

项目成果

期刊论文数量(0)
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Kim Sharp其他文献

Specific and potent inhibition of steroid hormone pre-receptor regulator AKR1C2 by perfluorooctanoic acid: Implications for androgen metabolism
  • DOI:
    10.1016/j.jsbmb.2024.106641
  • 发表时间:
    2025-02-01
  • 期刊:
  • 影响因子:
  • 作者:
    Andrea Andress Huacachino;Anna Chung;Kim Sharp;Trevor M. Penning
  • 通讯作者:
    Trevor M. Penning
KLF5 Is a Key Regulator of IMiD-Induced Neutropenia
  • DOI:
    10.1182/blood-2024-207135
  • 发表时间:
    2024-11-05
  • 期刊:
  • 影响因子:
  • 作者:
    Christina Simoglou Karali;Simone G Riva;Sally-Ann Clark;E. Ravza Gür;Nicholas Denny;Roman Doll;Anastasia Kosmidou;Assunta Adamo;Shady Adnan Awad;Srinivasa Adusumalli;Jiangpeikun Song;Sean Wen;Nikolaos Sousos;Eleni Louka;Nawshad Hayder;Kim Sharp;William E. Pierceall;Anjan Thakurta;Anita K. Gandhi;Patrick R. Hagner
  • 通讯作者:
    Patrick R. Hagner
Constructing a Computational Workflow for the Identification of Novel Cellular and Molecular Drivers of Human Granulopoiesis
  • DOI:
    10.1182/blood-2024-207224
  • 发表时间:
    2024-11-05
  • 期刊:
  • 影响因子:
  • 作者:
    Simone G Riva;Christina Simoglou Karali;E. Ravza Gür;Martin Sergeant;Edward Sanders;Sally-Ann Clark;Nicholas Denny;Roman Doll;Anastasia Kosmidou;Assunta Adamo;Shady Adnan Awad;Srinivasa Adusumalli;Jiangpeikun Song;Sean Wen;Nikolaos Sousos;Eleni Louka;Nawshad Hayder;Kim Sharp;William E. Pierceall;Anjan Thakurta
  • 通讯作者:
    Anjan Thakurta

Kim Sharp的其他文献

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{{ truncateString('Kim Sharp', 18)}}的其他基金

Calculation of Protein-ligand Binding Affinity
蛋白质-配体结合亲和力的计算
  • 批准号:
    0235440
  • 财政年份:
    2003
  • 资助金额:
    $ 28.5万
  • 项目类别:
    Standard Grant
Theoretical Studies of Antibody-Antigen Binding
抗体-抗原结合的理论研究
  • 批准号:
    9506900
  • 财政年份:
    1995
  • 资助金额:
    $ 28.5万
  • 项目类别:
    Continuing grant
Theoretical Studies of Antibody-Antigen Binding
抗体-抗原结合的理论研究
  • 批准号:
    9220477
  • 财政年份:
    1993
  • 资助金额:
    $ 28.5万
  • 项目类别:
    Standard Grant

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蛋白质折叠的理论研究
  • 批准号:
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Theoretical and computational studies of the biophysics of protein folding
蛋白质折叠生物物理学的理论和计算研究
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Computer simulations and theoretical studies of protein translocation
蛋白质易位的计算机模拟和理论研究
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  • 资助金额:
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Theoretical and computational studies of the biophysics of protein folding
蛋白质折叠生物物理学的理论和计算研究
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Theoretical Studies of Membrane Protein Folding
膜蛋白折叠的理论研究
  • 批准号:
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Theoretical Studies of Membrane Protein Folding
膜蛋白折叠的理论研究
  • 批准号:
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Theoretical Studies of Protein Folding
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  • 批准号:
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Theoretical Studies of Membrane Protein Folding
膜蛋白折叠的理论研究
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Theoretical studies of molecular mechanisms of abnormal protein aggregation
蛋白质异常聚集分子机制的理论研究
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CAREER: Theoretical studies of the relationship between the molecular structure and the mechanical properties of single protein molecules
职业:单个蛋白质分子的分子结构与机械性能之间关系的理论研究
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    0347862
  • 财政年份:
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