Collaborative Research: Energy Landscapes of Designed Cold Unfolding Proteins
合作研究:设计的冷展开蛋白质的能量景观
基本信息
- 批准号:2319819
- 负责人:
- 金额:$ 20.69万
- 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:2023-08-01 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Proteins are very large biological molecules synthesized in living organisms by linking hundreds or even thousands of amino acids to form a linear chain. Proteins are required for life and they are thus important targets for fundamental and biomedical research, including drug development, and biotechnology. Enzymes catalyzing biochemical reactions, protein drugs such as insulin, and antibodies conveying immunity are well-known examples. Importantly, the biological function of proteins is intimately linked to the many different three-dimensional shapes the linear chains can adopt, and these shapes depend critically on both temperature and pressure. The objective of this project is to enhance the understanding of the distinct shapes which proteins adopt at extreme conditions, that is, at very low temperatures below the freezing point of water and/or at very high pressures of several hundreds of atmospheres. This is required to understand life in the vast ecosystems existing under these conditions (e.g. in oceans and the polar regions), to understand how these shapes relate to protein function, protein related diseases, protein vaccine development, and protein drug formulation, and to enhance the engineering of bio-technologically and bio-medically important ‘cold adapted proteins’. The research contributes to develop rules to predict protein shapes and their energetic properties under such extreme conditions, and newly developed methodologies and computational tools will be made available to the broader scientific community. The project enables cross-interdisciplinary training of researchers, including scientists from underrepresented groups. To pursue this goal and to increase interest in STEM in general, Drs. Kuhlman and Szyperski, participate in well-established, major initiatives at their schools which are dedicated to promote inclusive communities, to retain underrepresented students in STEM and to mentor students. They also participate in NSF-funded research opportunities for undergraduates, and offer webinars on ‘linchpins’ for the understanding of (bio)physical chemistry and (bio)physics. Programming workshops focusing on methods for molecular modeling will also be offered.The relationship between the different three-dimensional molecular shapes of proteins dominating at different temperatures / pressures is related to their molecular energies and entropies, which are represented by so called ‘energy landscapes’. Proteins which tend to lose a well-defined shape at low temperatures have been named ‘cold unfolding proteins’. Research focuses on exploring and understanding the energy landscapes of such proteins. This includes the structural and thermodynamic properties of the ‘cold’ low energy / low entropy states, their transitions to other states and, in general, a more advanced understanding of protein pressure-temperature ‘phase diagrams’. A unique approach combining computational de novo protein design, cutting-edge biophysical techniques and molecular dynamics (MD) simulations is employed in order to specifically test central structural and thermodynamic hypotheses, namely that (i) a mixed hydrophobic / hydrophilic protein core results in a partially cold unfolded cold state in which water molecules form an integral part, (ii) this is manifested in complex energy landscapes, (iii) this results in a distinct thermodynamic signature for the formation of such cold states, and (iv) the co-operativity of the formation of the cold states decreases with an increasing hydrophilic content of the folded core. Moreover, the research lays the foundation to tackle the hypothesis that cold states can be functionally important, even at ambient conditions when they are lowly populated. Finally, new computational design protocols are developed which facilitate or enable the design of beta-sheet containing cold unfolding proteins, and the redesign of folded, naturally occurring proteins to congeners which unfold under extreme conditions in order to validate newly established principles. This project is supported 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.
蛋白质是生物体中合成的非常大的生物分子,通过连接数百甚至数千个氨基酸形成线性链。蛋白质是生命所必需的,因此它们是基础和生物医学研究的重要目标,包括药物开发和生物技术。催化生化反应的酶,胰岛素等蛋白质药物,以及传递免疫力的抗体都是众所周知的例子。重要的是,蛋白质的生物功能与线性链可以采用的许多不同的三维形状密切相关,而这些形状严重依赖于温度和压力。该项目的目标是加强对蛋白质在极端条件下,即在低于水的冰点的极低温度和/或在数百个大气压的极高压力下采用的独特形状的理解。这对于了解在这些条件下(例如海洋和极地地区)存在的巨大生态系统中的生命,了解这些形状与蛋白质功能、蛋白质相关疾病、蛋白质疫苗开发和蛋白质药物配方之间的关系,以及加强生物技术和生物医学上重要的“适应冷的蛋白质”的工程是必要的。这项研究有助于制定在这种极端条件下预测蛋白质形状及其能量性质的规则,新开发的方法和计算工具将提供给更广泛的科学界。该项目允许对研究人员进行跨学科培训,包括来自代表性不足群体的科学家。为了实现这一目标并提高对STEM的普遍兴趣,Kuhlman博士和Szyperski博士在他们的学校参与了一些成熟的重大倡议,这些倡议致力于促进包容性社区,留住STEM中代表性不足的学生,并指导学生。他们还参与美国国家科学基金会资助的本科生研究机会,并提供关于了解(生物)物理化学和(生物)物理的“关键”网络研讨会。在不同的温度/压力下,蛋白质的不同三维分子形状之间的关系与它们的分子能量和熵有关,这些能量和熵由所谓的能量景观表示。在低温下容易失去明确形状的蛋白质被称为“冷展开蛋白质”。研究的重点是探索和理解这类蛋白质的能量格局。这包括‘冷’低能/低熵态的结构和热力学性质,它们向其他态的转变,以及一般而言,对蛋白质压力-温度‘相图’的更深入的理解。采用了一种结合计算从头蛋白质设计、尖端生物物理技术和分子动力学(MD)模拟的独特方法来具体检验中心结构和热力学假设,即:(1)疏水/亲水混合蛋白质核导致部分冷展开的冷态,其中水分子是其中不可分割的一部分;(2)这体现在复杂的能量图景中;(3)这导致了这种冷态的形成有明显的热力学特征;(4)冷态形成的协作性随着折叠核心的亲水性含量的增加而降低。此外,这项研究为解决冷状态可能在功能上重要的假设奠定了基础,即使在人口较少的环境条件下也是如此。最后,开发了新的计算设计方案,促进或允许设计包含冷展开蛋白质的β-折叠,以及将折叠的、自然产生的蛋白质重新设计为在极端条件下展开的同种蛋白质,以验证新建立的原理。该项目由分子和细胞生物科学部的分子生物物理组支持。这一奖项反映了NSF的法定使命,并通过使用基金会的智力优势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
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Brian Kuhlman其他文献
Cages from coils
线圈制成的笼子
- DOI:
10.1038/nbt.2670 - 发表时间:
2013-09-10 - 期刊:
- 影响因子:41.700
- 作者:
Bryan S Der;Brian Kuhlman - 通讯作者:
Brian Kuhlman
Correction to "Catalysis by a De Novo Zinc-Mediated Protein Interface: Implications for Natural Enzyme Evolution and Rational Enzyme Engineering".
对“从头锌介导的蛋白质界面的催化:对天然酶进化和合理酶工程的影响”的更正。
- DOI:
- 发表时间:
2023 - 期刊:
- 影响因子:2.9
- 作者:
Bryan S. Der;David R Edwards;Brian Kuhlman - 通讯作者:
Brian Kuhlman
Analysis of Relative Binding Affinity Predictions for Protein-Protein Complexes
- DOI:
10.1016/j.bpj.2017.11.2262 - 发表时间:
2018-02-02 - 期刊:
- 影响因子:
- 作者:
Xavier Bonner;Brian Kuhlman;Hayretin Yumerefendi - 通讯作者:
Hayretin Yumerefendi
Rationally Designing Active Ga Protein Inhibitors for Signal Transduction Regulation
合理设计用于信号转导调节的活性Ga蛋白抑制剂
- DOI:
- 发表时间:
2020 - 期刊:
- 影响因子:0
- 作者:
Teppei NIide;David Thieker;Matthew Cummins;Brian Kuhlman - 通讯作者:
Brian Kuhlman
Conditional Mg<sup>2+</sup>-Assisted Catalysis: A Master Switching Motif Responsible for Differential Stability Suggests a General Transducing Mechanism
- DOI:
10.1016/j.bpj.2010.12.3128 - 发表时间:
2011-02-02 - 期刊:
- 影响因子:
- 作者:
Charles W. Carter;Violetta Weinreb;Li Li;Brian Kuhlman - 通讯作者:
Brian Kuhlman
Brian Kuhlman的其他文献
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{{ truncateString('Brian Kuhlman', 18)}}的其他基金
Collaborative Research: Design of Redox-Active Molybdenum Metalloproteins
合作研究:氧化还原活性钼金属蛋白的设计
- 批准号:
1403663 - 财政年份:2014
- 资助金额:
$ 20.69万 - 项目类别:
Standard Grant
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Cell Research
- 批准号:31224802
- 批准年份:2012
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Cell Research
- 批准号:31024804
- 批准年份:2010
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Cell Research (细胞研究)
- 批准号:30824808
- 批准年份:2008
- 资助金额:24.0 万元
- 项目类别:专项基金项目
Research on the Rapid Growth Mechanism of KDP Crystal
- 批准号:10774081
- 批准年份:2007
- 资助金额:45.0 万元
- 项目类别:面上项目
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