Residue Based Contributions to Protein Stability and Association

基于残留物对蛋白质稳定性和缔合的贡献

• 批准号: 9506793
• 负责人: PAUL E SMITH
• 金额: $ 28.66万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9506793
• 关键词: Affect; Agreement; Behavior; Computer Simulation; Country; Coupled; Data; Development; Disease; Environment; Free Energy; Hormones; Knowledge; Link; Molecular Conformation; Nature; Non-Insulin-Dependent Diabetes Mellitus; Peptide Fragments; Peptides; Physiological; Play; Process; Property; Protein Denaturation; Proteins; Residual state; Role; Sampling; Series; Structure; System; Temperature; Testing; Thermodynamics; base; biophysical analysis; combat; cost; enthalpy; experimental study; human disease; improved; islet amyloid polypeptide; mutant; non-Native; pressure; protein aggregation; protein aminoacid sequence; protein complex; protein misfolding; protein structure; public health relevance; simulation; theories; tool

 DESCRIPTION (provided by applicant): Studies of protein denaturation provide critical information concerning the forces that stabilize protein structure and other assemblies. This has a significant effect on our general understanding of the structure/function aspects of proteins that will directly impact our understanding of many diseases that are related to protein unfolding, misfolding, and aggregation. While the vast majority of studies have focused on the native state of proteins, the role of the denatured state is of equal importance. It is now generally accepted that the denatured state ensemble (DSE) is not random in nature but can possess residual native and non-native structure. While our knowledge of the properties of the native state has been advanced by a variety of experimental and simulation results, our understanding of the denatured state remains somewhat simplistic primarily due to the difficulties obtaining atomic level data from experiment, and our inability to determine the thermodynamic properties of the DSE from simulation. It is proposed that a combination of recent theoretical developments using Fluctuation Solution Theory, coupled with computer simulation approaches, can provide reliable data concerning the similarities and differences between denatured states generated by changes in pressure, temperature and composition at the residue level. There are three major aims to the proposed project. Aim 1: To Determine Residue Based Contributions to Protein Thermodynamics. Aim 2: To Determine the Thermodynamic Properties of Amylin and Mutant Amylin DSEs. Aim 3: To Determine the Effects of Environment on the Thermodynamic and Aggregation Properties of Small Peptide Sequences Derived from Amylin. The results of these studies will provide valuable information concerning the nature of the denatured state and the consequences for the role the DSE may play in a variety of diseases.

 描述（由申请人提供）：蛋白质变性的研究提供了有关稳定蛋白质结构和其他组装的力的关键信息，这对我们对蛋白质结构/功能方面的一般理解产生重大影响，从而直接影响我们对许多蛋白质的理解。与蛋白质展开有关的疾病， 虽然绝大多数研究都集中在蛋白质的天然状态，但变性状态的作用同样重要，现在人们普遍认为变性状态整体（DSE）本质上不是随机的，而是随机的。虽然通过各种实验和模拟结果，我们对天然状态的性质的了解有所提高，但我们对变性状态的理解仍然有些简单化，这主要是由于获得的困难。来自实验的原子级数据，以及我们无法通过模拟确定 DSE 的热力学性质，建议将最近的理论发展与波动解理论相结合，再加上计算机模拟方法，可以提供有关相似性和差异的可靠数据。拟议项目有三个主要目标：确定基于残留物对蛋白质热力学的贡献。胰淀素和突变胰淀素 DSE 的热力学性质 目标 3：确定环境对胰淀素衍生的小肽序列的热力学和聚集性质的影响 这些研究的结果将提供有关变性状态和突变体性质的有价值的信息。 DSE 在多种疾病中可能发挥的作用的后果。