Theoretical Studies of Protein Folding

智力价值这项活动的智力价值和目标主要不是预测诸如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例如，一个球形蛋白和从未折叠多肽链到最终折叠（天然）构象的途径（蛋白质折叠问题）。对于这样的理解，使用基于物理的方法，即仅基于基于势能和最近引入的熵效应（包括溶剂的作用）的自由能函数的全局优化，而不使用二级结构预测，同源性建模，线程化等。该项目的主要重点是将联合残基（UNRES）方法扩展到处理蛋白质- dna和蛋白质-蛋白质酶-底物复合物。为了实现这一目标，将会有UNRES的最终发展，用UNRES处理各种环境，在全原子水平上处理蛋白质结构，开发粗粒度的核酸模型，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-UNRES协议。更广泛的影响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构象热力学和折叠特性及其相互作用的基本理解，并将为开展这项研究的同事，以及与这些同事一起工作的博士后和访问科学家提供培训。提供了一个web服务器（chesshift），可在http://cheshift.com上获得，使核磁共振波谱学家能够获得理论上的C(α)-13化学位移来验证它们的结构。该项目得到了化学学部生命过程化学项目的共同资助

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