Theoretical Studies of Protein Folding

这项活动的智力价值和目标主要不是预测蛋白质和核酸等生物分子的结构，而是改进潜在的功能和算法，以便能够理解残基间相互作用如何决定三维结构，例如，球状蛋白质和从展开的多肽链到最终折叠（天然）构象的途径（蛋白质折叠问题）。 为了这样的理解，使用基于物理的方法，即，一个完全基于全局优化的自由能函数的基础上的势能和最近推出的熵效应（包括溶剂的作用），而不使用二级结构的预测，同源建模，线程等这个项目的主要重点是扩展的联合残基（UNRES）的方法来处理蛋白质-DNA和蛋白质-蛋白质酶-底物复合物。 为了实现这一目标，将最终开发UNRES，用UNRES处理各种环境，在全原子水平上处理蛋白质结构，开发核酸的粗粒度模型，处理蛋白质-核酸和蛋白质-蛋白质复合物，开发采样和分析算法，验证UNRES和核酸-该项目产生的更广泛的影响是，理论方法将提供对生物大分子的构象热力学和折叠特性及其相互作用的基本理解，并将提供培训，不仅是为了进行这项研究的同事，也是为了与这些同事一起工作的几位博士后和访问科学家。 提供了一个网络服务器（CheShift），可在http://cheshift.com上获得，使NMR光谱学家能够获得理论C（alpha）-13化学位移，以验证其结构。

Intellectual Merit The intellectual merit and the goal of this activity is not, primarily, to predict the structures of biomolecules such as proteins and nucleic acids but, rather to improve the potential functions and algorithms to be able to gain an understanding of how inter-residue interactions determine the three-dimensional structure of, for example, a globular protein and the pathways from the unfolded polypeptide chain to the final folded (native) conformation (the protein folding problem). For such an understanding, use is made of a physics-based approach, i.e., one based solely on the global optimization of a free energy function based on potential energy and on recently-introduced entropy effects (including the role of the solvent) without the use of secondary-structure predictions, homology modeling, threading, etc. The main focus of this project is the extension of the united-residue (UNRES) methodology to treat protein-DNA and protein-protein enzyme-substrate complexes. To accomplish this there will be the final development of UNRES, the treatment of various environments with UNRES, treatment of protein structures at the all-atom level, the development of a coarse-grained model of nucleic acids, the treatment of protein-nucleic acid and protein-protein complexes, the development of sampling and analysis algorithms and the validation of UNRES and nucleic acid-UNRES protocols.Broader ImpactThe broader impacts resulting from the project are that the theoretical approach will provide a basic understanding of the conformational thermodynamic, and folding properties of bio-macromolecules and their interaction with each other and will provide training, not only for the co-workers carrying out this research, but also for several postdocs and visiting scientists working together with these coworkers. A web server (CheShift), available at http://cheshift.com to enable NMR spectroscopists to obtain theoretical C(alpha)-13 chemical shifts to validate their structures, is provided.This project is receiving co-funding from the Chemistry of Life Processes program in the Chemistry Division