Investigation of Latent Free Energy in Noncovalent Networks

非共价网络中潜在自由能的研究

基本信息

  • 批准号:
    9330920
  • 负责人:
  • 金额:
    $ 36.55万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-08-15 至 2020-07-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Noncovalent networks (NCNs) in proteins play a critical role in biological function: communication through NCNs contributes to ligand binding, catalysis, allostery, and signal transduction, but the mechanisms by which NCNs contribute to these processes is not generally recognized. One possible mechanism for communication through a network is via the storage and release of latent free energy. Notably, each individual noncovalent interaction in an NCN is not necessarily optimized; instead, the NCN as a whole is optimized within the constraints of the protein. Because of this, NCNs store latent free energy. This provides the thermodynamic driving force for a protein to respond when it contacts an external stimulus, resulting in a downstream outcome. Changes in the balance of forces in the NCN result in the release of latent free energy, but the molecular mechanisms by which this occurs are poorly understood. Despite the critical role NCNs play in biological function, they are difficult to study in complex biological systems. However, simple model systems for molecular recognition generally do not encode enough complexity to adequately model the properties of a NCN. Herein, we propose to use two protein-like supramolecular assemblies of intermediate complexity to study the role of latent free energy in noncovalent network gated protein actuation, including responses to structural mutations (Aim 1) and recognition of a guest via induced-fit binding (Aim 2). These systems include a peptidic catenane and a peptidic macrocyclic host containing multiple beta-turns, intra- and interstrand H-bonds, and aromatic interactions that are all in communication. In the catenane, we will determine how a specific change in one part of a NCN can be compensated for (or not) by the rest of the network, and thus provide insight into mechanisms for storing and releasing latent free energy (Aim 1). The effect of mutations in each region of the network will be assessed experimentally and computationally to probe the structure, dynamics, and thermodynamics of the resultant catenane. Both enthalpic and entropic mechanisms for responding to a stimulus will be investigated. The host-guest system (Aim 2) will be utilized to investigate the coupling of the NCN in the host to the binding affinity of the guest. Stabilization of a protein's NCN upon binding has been proposed to provide significant enhancement of binding affinities (i.e. streptavidin-biotin). We will test this hypothesis by tunin the stability of the NCN in the host and experimentally and computationally characterizing its structure and response to a guest. Together, these studies will elucidate mechanisms by which NCNs utilize latent free energy in protein actuation and will provide a new conceptual model for protein function with applications to protein design and inhibitor development.
 描述(由申请人提供):蛋白质中的非共价网络(NCN)在生物学功能中发挥关键作用:通过NCN进行的通信有助于配体结合、催化、变构和信号转导,但NCN促进这些过程的机制尚未得到普遍认可。通过网络进行通信的一种可能机制是通过潜在自由能的存储和释放。值得注意的是,NCN中的每个单独的非共价相互作用不一定是优化的;相反,NCN作为一个整体在蛋白质的约束下进行优化。正因为如此,NCN储存潜在的自由能。这为蛋白质提供了热力学驱动力,使其在接触外部刺激时做出反应,从而产生下游结果。NCN中力平衡的变化导致潜在自由能的释放,但对此发生的分子机制知之甚少。尽管NCN在生物功能中发挥着关键作用,但它们很难在复杂的生物系统中进行研究。然而,用于分子识别的简单模型系统通常不编码足够的复杂性以充分模拟NCN的性质。在此,我们建议使用两个蛋白质样的超分子组装的中间复杂性,研究潜在的自由能在非共价网络门控蛋白质驱动的作用,包括响应结构突变(目标1)和识别的客人通过诱导适合结合(目标2)。这些系统包括肽索烃和肽大环主体,所述肽大环主体含有多个β-转角、链内和链间H-键以及芳香族相互作用,所述相互作用全部处于通信中。在链烷中,我们将确定NCN的一部分中的特定变化如何被网络的其余部分补偿(或不补偿),从而提供对存储和释放潜在自由能的机制的见解(目标1)。在网络的每个区域中的突变的效果将通过实验和计算来评估,以探测所得索烃的结构、动力学和热力学。我们将研究对刺激作出反应的熵和熵机制。主体-客体系统(目标2)将用于研究主体中NCN与客体结合亲和力的偶联。已经提出在结合时稳定蛋白质的NCN以提供结合亲和力的显著增强(即链霉亲和素-生物素)。我们将通过调节NCN在宿主中的稳定性并通过实验和计算表征其结构和对客体的响应来测试这一假设。总之,这些研究将阐明NCN在蛋白质驱动中利用潜在自由能的机制,并将为蛋白质功能提供新的概念模型,并应用于蛋白质设计和抑制剂开发。

项目成果

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MARCEY L WATERS其他文献

MARCEY L WATERS的其他文献

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{{ truncateString('MARCEY L WATERS', 18)}}的其他基金

Mechanistic Investigation and Engineering of Histone Reader Proteins
组蛋白阅读器蛋白的机制研究和工程
  • 批准号:
    10405225
  • 财政年份:
    2022
  • 资助金额:
    $ 36.55万
  • 项目类别:
Mechanistic Investigation and Engineering of Histone Reader Proteins
组蛋白阅读器蛋白的机制研究和工程
  • 批准号:
    10687280
  • 财政年份:
    2022
  • 资助金额:
    $ 36.55万
  • 项目类别:
Mechanistic Studies and Engineering of Histone PTM Reader Proteins
组蛋白 PTM Reader 蛋白的机制研究和工程
  • 批准号:
    10208349
  • 财政年份:
    2017
  • 资助金额:
    $ 36.55万
  • 项目类别:
Origins of Ligand Binding and Selectivity in Methyllysine Reader and Writer Proteins
甲基赖氨酸读取和写入蛋白中配体结合和选择性的起源
  • 批准号:
    9742021
  • 财政年份:
    2017
  • 资助金额:
    $ 36.55万
  • 项目类别:
Mechanistic Studies and Engineering of Histone PTM Reader Proteins
组蛋白 PTM Reader 蛋白的机制研究和工程
  • 批准号:
    10581037
  • 财政年份:
    2017
  • 资助金额:
    $ 36.55万
  • 项目类别:
Investigation of Latent Free Energy in Noncovalent Networks
非共价网络中潜在自由能的研究
  • 批准号:
    9104526
  • 财政年份:
    2016
  • 资助金额:
    $ 36.55万
  • 项目类别:
Aromatic Interactions in Nucleotide/Carbohydrate Binding
核苷酸/碳水化合物结合中的芳香族相互作用
  • 批准号:
    7184319
  • 财政年份:
    2005
  • 资助金额:
    $ 36.55万
  • 项目类别:
Aromatic Interactions in Nucleotide/Carbohydrate Binding
核苷酸/碳水化合物结合中的芳香族相互作用
  • 批准号:
    7013957
  • 财政年份:
    2005
  • 资助金额:
    $ 36.55万
  • 项目类别:
Aromatic Interactions in Nucleotide/Carbohydrate Binding
核苷酸/碳水化合物结合中的芳香族相互作用
  • 批准号:
    6854888
  • 财政年份:
    2005
  • 资助金额:
    $ 36.55万
  • 项目类别:
Aromatic Interactions in Nucleotide/Carbohydrate Binding
核苷酸/碳水化合物结合中的芳香族相互作用
  • 批准号:
    7343268
  • 财政年份:
    2005
  • 资助金额:
    $ 36.55万
  • 项目类别:

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