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
• 负责人: Rohit Pappu
• 金额: $ 42.57万
• 依托单位: Washington University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0416766&HistoricalAwards=false
• 关键词: Studying; Origin; Conformational; Preferences; Unfolded

The objective of this project is to develop a predictive model for the experimentally observed conformational preferences of unfolded proteins. Tiffany and Krimm proposed that unfolded proteins are an ensemble of conformations, each built of local segments that fluctuate in an uncorrelated manner about left-handed polyproline II (PII) helices. Recent experimental results support this hypothesis. PII-like conformations are preferred for a variety of model peptides in water, although the PII-content itself varies with amino acid sequence, solvent, and temperature. How are these preferences realized in the absence of cooperative interactions that stabilize the folded state? For over four decades the random-coil model has been the dominant paradigm for unfolded proteins. This model does not help explain the origin of specific local conformational preferences, nor does it offer insights into the role of such preferences for protein folding and stability. It is imperative that an appropriate framework be developed to account for the experimentally observed preferences of unfolded proteins. Such an endeavor is of crucial importance in understanding the physical principles that underlie the evolution of foldable and functional amino acid sequences. Recent results suggest that there are two distinct determinants of conformational preferences in unfolded proteins. The realization of distinct conformational basins is mainly determined by excluded volume effects. Conversely, the relative stabilities of these conformational basins encoded by steric considerations can be noticeably modulated by solvation and other thermodynamic parameters such as temperature and pressure. The goal of this research is to study the PII content of short model peptides and small proteins as a function of amino acid sequence, chain length, and milieu. To this end, molecular simulations based on both simple and sophisticated all-atom potential functions will be performed. The validity of all theoretical calculations will be tested by comparisons with experimental data. The PI is actively involved in recruiting and training undergraduate and graduate students in areas of biophysics, bioengineering, and computational biology. The course contents are cross-disciplinary and students who take the courses come from a variety of disciplines ranging from the basic to applied sciences. The PI is also actively working on the design of novel algorithms, ideas, and tools for molecular simulation. Computational technologies developed in the PI's group have been and will continue to be integrated with resources that are made available to the scientific community by members of the Center for Computational Biology at Washington University.

本项目的目的是开发一个预测模型的实验观察到的未折叠蛋白质的构象偏好。Tiffany和Krimm提出，未折叠蛋白质是构象的集合，每个构象都由局部片段组成，这些片段以不相关的方式围绕左手聚脯氨酸II（PII）螺旋波动。最近的实验结果支持这一假设。尽管PII含量本身随氨基酸序列、溶剂和温度而变化，但对于水中的各种模型肽，PII样构象是优选的。在没有稳定折叠状态的合作相互作用的情况下，这些偏好是如何实现的？四十多年来，无规卷曲模型一直是未折叠蛋白质的主导范式。这个模型并不能帮助解释特定的局部构象偏好的起源，也不能深入了解这种偏好对蛋白质折叠和稳定性的作用。当务之急是要开发一个适当的框架来解释实验观察到的未折叠蛋白质的偏好。这样的奋进对于理解可折叠和功能性氨基酸序列进化的物理原理至关重要。最近的研究结果表明，有两个不同的决定因素的构象偏好展开的蛋白质。不同构象盆地的实现主要取决于排除体积效应。相反，这些构象盆地编码的空间考虑的相对稳定性可以明显调制的溶剂化和其他热力学参数，如温度和压力。 本研究的目的是研究短模型肽和小蛋白质的PII含量作为氨基酸序列、链长度和环境的函数。为此，将进行基于简单和复杂的全原子势函数的分子模拟。所有理论计算的有效性将通过与实验数据的比较来检验。PI积极参与招募和培训生物物理学，生物工程和计算生物学领域的本科生和研究生。课程内容是跨学科的，参加课程的学生来自从基础科学到应用科学的各种学科。 PI还积极致力于分子模拟的新算法、思想和工具的设计。PI小组开发的计算技术已经并将继续与华盛顿大学计算生物学中心成员向科学界提供的资源相结合。