Impact of charge regulation on conformational and phase equilibria of intrinsically disordered proteins

电荷调节对本质无序蛋白质构象和相平衡的影响

基本信息

  • 批准号:
    2227268
  • 负责人:
  • 金额:
    $ 120.12万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
    Standard Grant
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-03-01 至 2027-02-28
  • 项目状态:
    未结题

项目摘要

Cells are organized into distinct compartments, and many of these compartments are defined by different acidity. An environment rich in protons can change the charge on proteins in cells if the proteins have amino acids that are ionizable. Changes to charge states of proteins that arise from the association or dissociation of protons can control how proteins in cells respond to specific types of signals such as environmental factors that induce changes to salt or proton concentrations. Research in this project will leverage new methods to study how specific proteins, known as intrinsically disordered proteins, are modified by the uptake or release of protons based on the acidity of the solution. Studies carried out as part of the project will lead to an improved understanding of how alterations to charge states of proteins influence their functions. This work is important because charge-mediated interactions are central to a variety of protein functions including the recognition of one protein by another. Given the unique nature of the technological advances that are driving research in the project, there will be novel training opportunities at the intersection of computation and experiment in the broad area of molecular biophysics. Findings from the project will be incorporated into materials of courses for undergraduates. Further, key personnel who are involved in the project will work closely with students from inner city middle and high-schools to explain how pH and a better understanding of acid-base equilibria will drive new research frontiers that emerge from the project. The blend of computation and experiment, driven in part by the development of novel computational tools, including machine learning modules, will create new workflows for solving challenging problems in molecular biophysics. These modules will be incorporated into instructional modules for research trainees and students in molecular biophysics.The goal of the project is to understand how the exchange of protons between ionizable residues and the accumulation of solution ions around these residues contribute to the charge states and conformations of intrinsically disordered proteins (IDPs). Currently, our understanding of the form, functions, and phase behaviors of IDPs is limited by the simplifying assumption that charge states of ionizable residues are fixed by the pKa values of model compounds. The proposed work rests on the principle that conformational fluctuations engender changes to local microenvironments of ionizable residues. These local heterogeneities can induce exchange of protons among titratable sites. This can also induce preferential accumulation of solution ions around ionizable residues. A key advance that drives the investigations is the recent development of the q-canonical ensemble, which is a formal and rigorous statistical physics-based description of the joint effects of charge state and conformational heterogeneity. Importantly, an integrated experimental and computational pipeline has been developed and this allows one to leverage the structure of the q-canonical ensemble to quantify the effects of proton association or dissociation, known as charge regulation, and its interplay with the effects of solution ions through charge renormalization. Approaches that rest on the formal decoupling between measurements of charge and conformation, will allow for the incorporation of information derived from potentiometric titrations and measurements of conformational or phase equilibria into simulations. This, when anchored by experimental data, will lead to a full description of the ensemble of charge state and conformations that are accessible at different solution conditions. The approaches are novel, the focus is unique, and the insights to be generated from the project are likely to be unprecedented. This project is funded by the Molecular Biophysics Cluster in the Division of Molecular and Cellular Biosciences.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
细胞被组织成不同的区室,其中许多区室由不同的酸度定义。如果细胞中的蛋白质含有可电离的氨基酸,则富含质子的环境可以改变蛋白质上的电荷。由质子缔合或解离引起的蛋白质电荷状态的变化可以控制细胞中的蛋白质如何响应特定类型的信号,例如诱导盐或质子浓度变化的环境因素。该项目的研究将利用新方法来研究特定蛋白质(称为内在无序蛋白质)如何通过基于溶液酸度的质子吸收或释放来进行修饰。作为该项目的一部分进行的研究将有助于更好地了解蛋白质电荷状态的改变如何影响其功能。这项工作很重要,因为电荷介导的相互作用是各种蛋白质功能的核心,包括一种蛋白质对另一种蛋白质的识别。鉴于推动该项目研究的技术进步的独特性质,在分子生物物理学的广泛领域,计算和实验的交叉点将有新的培训机会。该项目的研究结果将纳入本科生课程材料。此外,参与该项目的关键人员将与来自市中心初中和高中的学生密切合作,解释pH值和更好地了解酸碱平衡将如何推动该项目出现的新研究前沿。计算和实验的融合,部分是由包括机器学习模块在内的新型计算工具的开发驱动的,将为解决分子生物物理学中具有挑战性的问题创造新的工作流程。这些单元将被纳入分子生物物理学研究实习生和学生的教学单元,该项目的目标是了解可电离残基之间的质子交换和这些残基周围溶液离子的积累如何有助于内在无序蛋白质(IDP)的电荷状态和构象。目前,我们的理解的形式,功能和相行为的IDPs是有限的简化假设,电离残基的电荷状态是固定的pKa值的模型化合物。拟议的工作依赖于构象波动引起局部可电离残基微环境变化的原则。这些局部不均匀性可诱导可滴定位点之间的质子交换。这也可以诱导溶液离子在可电离残留物周围的优先积累。推动调查的一个关键进展是最近发展的q-正则系综,这是一个正式的和严格的统计物理为基础的电荷状态和构象异质性的联合影响的描述。重要的是,已经开发了一个集成的实验和计算管道,这使得人们能够利用q-正则系综的结构来量化质子缔合或解离的影响(称为电荷调节),及其与溶液离子效应的相互作用通过电荷重整化。的方法,其余的电荷和构象的测量之间的正式去耦,将允许纳入来自电位滴定和测量的构象或相平衡到模拟的信息。这一点,当锚定的实验数据,将导致一个完整的描述,在不同的解决方案条件下访问的电荷状态和构象的合奏。这些方法是新颖的,重点是独特的,从项目中产生的见解可能是前所未有的。该项目由分子和细胞生物科学部的分子生物物理学小组资助。该奖项反映了NSF的法定使命,并通过使用基金会的知识价值和更广泛的影响审查标准进行评估,被认为值得支持。

项目成果

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Rohit Pappu其他文献

Decoding Sequence-Ensemble Relationships of IDPS
  • DOI:
    10.1016/j.bpj.2013.11.063
  • 发表时间:
    2014-01-28
  • 期刊:
  • 影响因子:
  • 作者:
    Rohit Pappu
  • 通讯作者:
    Rohit Pappu
Gelation and Vitrification of Tardigrade IDPs
  • DOI:
    10.1016/j.bpj.2017.11.3065
  • 发表时间:
    2018-02-02
  • 期刊:
  • 影响因子:
  • 作者:
    Thomas C. Boothby;Samantha Piszkiewicz;Aakash Mehta;Alexandra Brozena;Hugo Tapia;Doug Koshland;Alex Holehouse;Rohit Pappu;Bob Goldstein;Gary Pielak
  • 通讯作者:
    Gary Pielak
Effects Of Sequence And Conformational Contexts In Polyglutamine Aggregation
  • DOI:
    10.1016/j.bpj.2008.12.2993
  • 发表时间:
    2009-02-01
  • 期刊:
  • 影响因子:
  • 作者:
    Rohit Pappu
  • 通讯作者:
    Rohit Pappu
A Protein Condensate Drives Actin-Independent Endocytosis
  • DOI:
    10.1016/j.bpj.2018.11.894
  • 发表时间:
    2019-02-15
  • 期刊:
  • 影响因子:
  • 作者:
    Stephen Michnick;Louis-Philippe Bergeron-Sandoval;Rohit Pappu;Paul François;Adam G. Hendricks;Allen J. Ehrlicher;Hossein Khadivi Heris
  • 通讯作者:
    Hossein Khadivi Heris

Rohit Pappu的其他文献

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{{ truncateString('Rohit Pappu', 18)}}的其他基金

DMREF: Collaborative Research on High throughput Exploration of Sequence Space of Peptide Polymers that Exhibit Aqueous Demixing Phase Behavior
DMREF:表现出水相分层行为的肽聚合物序列空间高通量探索的合作研究
  • 批准号:
    1729783
  • 财政年份:
    2017
  • 资助金额:
    $ 120.12万
  • 项目类别:
    Standard Grant
Multiscale Modeling of Phase Transitions Driven by Multivalency and Disordered Proteins
多价和无序蛋白质驱动的相变的多尺度建模
  • 批准号:
    1614766
  • 财政年份:
    2016
  • 资助金额:
    $ 120.12万
  • 项目类别:
    Continuing Grant
Conference: 2012 Intrinsically Disordered Proteins GRC; to be held July 8-13, 2012 in West Dover, VT
会议:2012 本质无序蛋白质 GRC;
  • 批准号:
    1242441
  • 财政年份:
    2012
  • 资助金额:
    $ 120.12万
  • 项目类别:
    Standard Grant
Phase Behavior of Intrinsically Disordered Proteins
本质无序蛋白质的相行为
  • 批准号:
    1121867
  • 财政年份:
    2011
  • 资助金额:
    $ 120.12万
  • 项目类别:
    Continuing Grant
Conformational Eequilibria of Intrinsically Disordered Proteins
本质无序蛋白质的构象平衡
  • 批准号:
    0718924
  • 财政年份:
    2007
  • 资助金额:
    $ 120.12万
  • 项目类别:
    Continuing Grant
Studying the Origin of Conformational Preferences in Unfolded Proteins
研究未折叠蛋白质构象偏好的起源
  • 批准号:
    0416766
  • 财政年份:
    2004
  • 资助金额:
    $ 120.12万
  • 项目类别:
    Standard Grant

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PIP2 结合位点的动态变化及其对癫痫相关 KCNQ/Kv7 通道的轴突靶向和功能的影响
  • 批准号:
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