Energetics of Channel-Bilayer Interactions

通道双层相互作用的能量

• 批准号: 7922787
• 负责人: OLAF S. ANDERSEN
• 金额: $ 41.85万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7922787
• 关键词: Accounting; Address; Adsorption; Affect; Alamethicin; Binding; Biological; Charge; Cholesterol; Complex; Consensus; Coupled; Coupling; Descriptor; Elasticity; Electrostatics; Engineering; Environment; Equilibrium; Free Energy; Frustration; Gramicidin; Group Structure; Head; Heterogeneity; Intervention; Ion Channel; Lateral; Length; Lipid Bilayers; Lipids; Measures; Membrane; Membrane Fluidity; Membrane Proteins; Modeling; Nonesterified Fatty Acids; Peptides; Pharmaceutical Preparations; Phase; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositol Phosphates; Phosphatidylinositols; Phospholipids; Positioning Attribute; Property; Protein Binding; Protein Conformation; Proteins; Regulation; Relative (related person); Research; Solutions; Stress; System; Thick; Transducers; Uncertainty; Unsaturated Fatty Acids; analog; antimicrobial; antimicrobial peptide; base; cost; design; flexibility; monolayer; novel; pressure; protein function; public health relevance; research study; theories

DESCRIPTION (provided by applicant): Membrane protein function is regulated by changes in the lipid composition of the host bilayer. This regulation, though well-established, remains enigmatic as evident by the many terms that are used to describe its mechanistic basis: changes in bilayer fluidity; changes in bilayer compression or curvature frustration energies, which can be combined into the bilayer deformation energy; changes in lateral pressure profile or lipid packing stress; changes in bilayer free volume; changes in bilayer stiffness. Changes in bilayer fluidity cannot be a major mechanism, as they cannot account for changes in the equilibrium distribution among different protein conformations. The remaining descriptors represent different approaches to parameterize the interactions among bilayer-forming lipids and between the lipids and the embedded proteins. The objective of the proposed studies is to develop an energetic framework for describing the functional consequences of the hydrophobic coupling between membrane-spanning proteins and their host bilayer, and to evaluate how membrane protein-bilayer interactions can be manipulated pharmacologically. The project is based on the notion of an elastic bilayer, in which membrane proteins undergo conformational changes that perturb the adjacent bilayer. This perturbation incurs an energetic cost that contributes to the overall free energy difference of the protein conformational changes. The protein-bilayer hydrophobic coupling therefore causes protein function to vary with changes in lipid bilayer material properties (thickness, lipid intrinsic curvature and the bilayer elastic compression and bending moduli), and the lipid bilayer becomes an allosteric regulator of membrane protein function. Changes in bilayer elastic properties can be characterized in terms of a restoring force that pulls on the embedded channel to minimize the bilayer deformation energy. Changes in this force can be measured using bilayer-embedded for transducers. The experiments will address the following questions. How good is the elastic bilayer model in predicting the energetic cost of channel-bilayer bilayer interactions? Can it be applied to multi-component lipid bilayers? This will be examined using phospholipids (alone or in combination), which form bilayers that differ in thickness and lipid intrinsic curvature. How do small amphiphiles, such as free fatty acids, antimicrobial peptides and other membrane-active molecules alter lipid bilayer material properties and membrane protein function? This will be examined by probing how selected drugs alter bilayer properties, and relating this information to more complex systems. Can PI(4,5)P2 (and other phosphoinositides) alter membrane protein function through local changes in bilayer material properties? This will be examined using gramicidin analogues with appropriately designed phosphoinositide-binding domains. Can the channel-bilayer hydrophobic mismatch drive a lateral association between bilayer-spanning channels? This will be studied by examining the relative stabilization of double- barreled channels of different lengths imbedded in bilayers of different thicknesses. PUBLIC HEALTH RELEVANCE: The proposed studies will examine how important molecules, such as poly-unsaturated fatty acids (PUFAs), alter lipid bilayer properties and thereby membrane protein function. The experimental approach is based on the notion of an elastic bilayer, which contributes to the regulation of membrane protein function through hydrophobic coupling to the embedded membrane proteins. The bilayer elasticity can be altered by the adsorption of PUFAs and other membrane-active compounds, which provides a mechanistic basis for the changes in membrane protein function.

描述（由申请人提供）：膜蛋白功能受宿主双层脂质组成变化的调节。这种调节，虽然已经建立，但仍然是谜一样的，因为许多术语被用来描述其机械基础：双层流动性的变化;双层压缩或曲率挫折能量的变化，可以组合成双层变形能量;侧压力分布或脂质包装应力的变化;双层自由体积的变化;双层刚度的变化。双层流动性的变化不能成为主要机制，因为它们不能解释不同蛋白质构象之间平衡分布的变化。其余的描述符代表不同的方法来参数化形成双层的脂质之间的相互作用和脂质和嵌入的蛋白质之间。拟议的研究的目的是开发一个充满活力的框架，用于描述跨膜蛋白和它们的宿主双层之间的疏水耦合的功能后果，并评估如何膜蛋白-双层相互作用可以被操纵。该项目是基于弹性双层的概念，其中膜蛋白经历构象变化，扰动相邻的双层。这种扰动引起的能量成本，有助于蛋白质构象变化的整体自由能差。因此，蛋白质-双层疏水偶联导致蛋白质功能随着脂质双层材料性质（厚度、脂质固有曲率和双层弹性压缩和弯曲模量）的变化而变化，并且脂质双层成为膜蛋白质功能的变构调节剂。双层弹性性质的变化可以根据恢复力来表征，所述恢复力拉动嵌入的通道以使双层变形能最小化。可以使用双层嵌入式传感器来测量该力的变化。实验将解决以下问题。弹性双层模型在预测通道-双层相互作用的能量消耗方面有多好？它能应用于多组分脂质双层吗？这将使用磷脂（单独或组合）进行检查，磷脂形成厚度和脂质固有曲率不同的双层。小分子两亲物，如游离脂肪酸，抗菌肽和其他膜活性分子如何改变脂质双层材料的性质和膜蛋白的功能？这将通过探测所选药物如何改变双层性质，并将此信息与更复杂的系统进行研究。PI（4，5）P2（和其他磷酸肌醇）能通过双层材料性质的局部变化改变膜蛋白功能吗？这将使用具有适当设计的磷酸肌醇结合结构域的短杆菌肽类似物进行检查。通道-双层疏水性错配能否驱动跨双层通道之间的横向缔合？这将通过检查嵌入不同厚度双层中的不同长度的双管通道的相对稳定性来研究。公共卫生相关性：拟议的研究将研究重要分子，如多不饱和脂肪酸（PUFA），如何改变脂质双层特性，从而改变膜蛋白功能。实验方法是基于弹性双层的概念，其有助于通过与嵌入的膜蛋白的疏水偶联来调节膜蛋白功能。PUFA和其他膜活性化合物的吸附可以改变双层弹性，这为膜蛋白功能的变化提供了机制基础。