Theoretical Studies of Protein Folding

该项目由生物科学局分子和细胞生物科学部的分子生物学和数学和物理科学局化学部的理论和计算化学计划联合支持，目的是了解残基之间的相互作用如何决定球状蛋白质的三维结构，以及从展开的多肽链到最终折叠构象的路径。为了理解这种理解，使用了一种基于物理的方法，即仅基于势能函数(包括溶剂的作用)的全局优化，而不使用二级结构预测、同源建模、线程等。这种方法既需要可靠的势函数，也需要有效的全局优化程序；本项目涉及开发和改进所需的经验势函数。最初，使用联合剩余(UNRES)势函数。UNRES将通过包含熵的晶体计算得到改进。然后，通过对包含水化的全原子势函数进行Z-Score优化，将精化的UNRES势函数转换为全原子处理。UNRES势能函数正在得到改进，方法是利用朗之万动力学产生诱饵，并利用分级优化程序纳入熵努力。全原子势函数(包括广义的Born溶剂化模型)将通过与改进UNRES势函数相同的层次化优化程序来改进。搜索过程将通过改进构象空间退火法(CSA)进行。这项研究将提供对决定蛋白质构象和折叠性质的残基间相互作用的基本了解，并将为进行这项研究的两名同事，以及与这些同事一起工作的几名博士后和研究生提供培训。此外，正如在当前项目期间所做的那样(小组成员参与纽约州各地学校的8年级和9年级学生的外展职业探索)，小组的研究生和博士后成员将参加康奈尔大学面向小学生的扩展你的数学、科学和工程视野计划。

The objective of this project, jointly supported by Molecular Biophysics in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences and the Theoretical and Computational Chemistry Program in the Division of Chemistry in the Mathematical and Physical Sciences Directorate, is to gain an understanding of how inter-residue interactions determine the three-dimensional structure of a globular protein and the pathways from the unfolded polypeptide chain to the final folded conformation. For such an understanding, use is made of a physics-based approach, i.e. one based solely on the global optimization of a potential energy function (including the role of the solvent), without the use of secondary-structure predictions, homology modeling, threading, etc. Such an approach requires both a reliable potential function and an efficient procedure for global optimization; this project is concerned with the development and improvement of the required empirical potential function. Initially, a united-residue (UNRES) potential function is used. UNRES will be improved by crystal calculations, with inclusion of entropy. Then the refined UNRES potential function will be converted to an all-atom treatment by Z-score optimization of the all-atom potential function with inclusion of hydration. The UNRES potential function is being improved by generating decoys with Langevin dynamics and incorporating entropy efforts, using a hierarchical optimization procedure. The all-atom potential function (including a Generalized-Born solvation model) will be improved by the same hierarchical optimization procedure used to improve the UNRES potential function. The search procedures will be carried out by improvement of a Conformational Space Annealing (CSA) method.This research will provide a basic understanding of the role of the inter-residue interactions that determine the conformational and folding properties of proteins, and will provide training, not only for the two co-workers carrying out this research, but also for several postdocs and graduate students working together with these co-workers. Also, as was done during the current project period (when members of the group participated in outreach career exploration by 8th and 9th grade students from schools across New York State), graduate student and postdoc members of the group will participate in the Expanding Your Horizons in Math, Science, and Engineering program of Cornell University for primary school students.