Understanding the role of membrane environment on membrane protein association and function

了解膜环境对膜蛋白关联和功能的作用

• 批准号: 1714888
• 负责人: Blake Mertz
• 金额: $ 39.48万
• 依托单位: West Virginia University Research Corporation
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1714888&HistoricalAwards=false
• 关键词: Understanding; role; membrane; environment; protein

Membrane proteins act as the gatekeepers of the cell, playing an intimate role in most biological functions. A detailed molecular description of how the membrane environment modulates association of membrane proteins will provide fundamental insights into biological processes that are linked to fields such as biomedicine, pharmaceuticals, and solar energy harvesting. Computational modeling approaches will be utilized to determine the effect of the cellular membrane on the association of membrane proteins. The advantage of computational modeling is that it can characterize the dynamics of association and dissociation of membrane proteins. The membrane protein to be studied is proteorhodopsin (PR), a protein common to microbial life in marine ecosystems. PR is a critical to survival of these microbes and their role in the carbon cycle may directly affect the ability of the ocean to accommodate fluctuations in the atmospheric environment. This project aims to model the effects of changing cell membrane composition on the function of PR and its association into multi-component complexes. Results will aid the biophysics community in their understanding of the relationship between cell membrane environment and protein function. In addition to training graduate and undergraduate students, the proposed research will involve professors and students from primarily undergraduate institutions in West Virginia. These students are from Appalachia, a traditionally underrepresented region in STEM fields. Thus, this project will develop long-term relationships for increasing student involvement in scientific research and encourage them to pursue careers in STEM fields.The specific objectives of this project are the characterization of the structure-function relationship of proton pumping in proteorhodopsin, the identification of key monomer-monomer interactions during oligomerization of this protein, and, determination of the relationship between membrane environment and oligomerization. Several molecular dynamics (MD) simulation approaches will be used to pursue each objective. Determination of conformational changes in PR activation will elucidate how proton pumping occurs. Characterization of the relationship between membrane composition and oligomerization will reconcile conflicting hypotheses on oligomerization of PR in native-like and non-native membrane environments. This will also contribute to knowledge of membrane protein interactions in systems such as bacterial inner membranes. Insights obtained will provide a general framework for interpretation and design of detergent-membrane protein experiments, since detergent solubilization is the de facto method for these studies.

膜蛋白作为细胞的守门人，在大多数生物功能中发挥着重要作用。膜环境如何调节膜蛋白的关联的详细分子描述将提供与生物医学，制药和太阳能收集等领域相关的生物过程的基本见解。将利用计算建模方法来确定细胞膜对膜蛋白结合的影响。 计算建模的优点是它可以表征膜蛋白的缔合和解离的动力学。待研究的膜蛋白是蛋白视紫质（PR），这是海洋生态系统中微生物生命的一种常见蛋白质。PR对这些微生物的生存至关重要，它们在碳循环中的作用可能直接影响海洋适应大气环境波动的能力。该项目旨在模拟改变细胞膜组成对PR功能及其与多组分复合物的关联的影响。研究结果将有助于生物物理学界理解细胞膜环境与蛋白质功能之间的关系。除了培训研究生和本科生外，拟议的研究还将涉及西弗吉尼亚州主要本科院校的教授和学生。这些学生来自阿巴拉契亚，这是一个传统上在STEM领域代表性不足的地区。因此，本项目将发展长期的关系，以增加学生参与科学研究，并鼓励他们追求在STEM领域的职业生涯。本项目的具体目标是表征蛋白质视紫红质中质子泵的结构-功能关系，识别这种蛋白质寡聚化过程中的关键单体-单体相互作用，以及，确定膜环境和低聚反应之间的关系。将使用几种分子动力学（MD）模拟方法来实现每个目标。PR激活的构象变化的测定将阐明质子泵是如何发生的。膜组成和寡聚化之间的关系的表征将调和PR在原生和非原生膜环境中寡聚化的相互冲突的假设。这也将有助于了解膜蛋白相互作用的系统，如细菌内膜。所获得的见解将提供一个一般的框架，解释和设计的洗涤剂膜蛋白实验，因为洗涤剂溶解是事实上的方法，这些研究。

项目成果

Allosteric Effects of the Proton Donor on the Microbial Proton Pump Proteorhodopsin

• DOI: 10.1016/j.bpj.2018.08.028
• 发表时间: 2018-10-02
• 期刊: BIOPHYSICAL JOURNAL
• 影响因子: 3.4
• 作者: Faramarzi, Sadegh;Feng, Jun;Mertz, Blake
• 通讯作者: Mertz, Blake

Theoretical Insights into the Mechanism of Wavelength Regulation in Blue-Absorbing Proteorhodopsin

吸蓝蛋白视紫红质波长调节机制的理论见解

• DOI: 10.1021/acs.jpcb.9b08189
• 发表时间: 2019
• 期刊: The Journal of Physical Chemistry B
• 作者: Lee, Choongkeun;Sekharan, Sivakumar;Mertz, Blake
• 通讯作者: Mertz, Blake

Bacterial Analogs to Cholesterol Affect Dimerization of Proteorhodopsin and Modulates Preferred Dimer Interface

胆固醇的细菌类似物影响蛋白视紫红质的二聚化并调节优选的二聚体界面

• DOI: 10.1021/acs.jctc.0c01174
• 发表时间: 2021
• 期刊: Journal of Chemical Theory and Computation
• 影响因子: 5.5
• 作者: Sefah, Eric;Mertz, Blake
• 通讯作者: Mertz, Blake