Studying the Origin of Conformational Preferences in Unfolded Proteins

本项目的目的是为未折叠蛋白质的实验观察到的构象偏好建立一个预测模型。Tiffany和Krimm提出，未折叠的蛋白质是一个构象的集合，每个构象都是由左旋脯氨酸II （PII）螺旋上以不相关的方式波动的局部片段组成的。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、溶剂和温度的变化而变化，但在水中的各种模型肽首选pii样构象。在缺乏稳定折叠态的合作互动的情况下，这些偏好是如何实现的？四十多年来，随机线圈模型一直是未折叠蛋白质的主要范式。这个模型不能帮助解释特定的局部构象偏好的起源，也不能提供这种偏好对蛋白质折叠和稳定性的作用的见解。必须建立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。这种努力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，在未折叠的蛋白质中，有两个不同的构象偏好决定因素。不同构象盆地的实现主要取决于排除体积效应。相反，这些构象盆地的相对稳定性可以通过溶剂化和其他热力学参数（如温度和压力）来明显调节。本研究的目的是研究短模型肽和小蛋白的PII含量与氨基酸序列、链长和环境的关系。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积极参与招收和培训生物物理学、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，选修课程的学生来自从基础科学到应用科学的各个学科。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。

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.