Theoretical Studies of Protein Folding

该项目的目标是由生物科学理事会分子和细胞生物科学部的分子生物物理学以及数学和物理科学理事会化学部的理论和计算化学计划共同支持，是为了了解残基间的相互作用如何决定这三个-球状蛋白的三维结构和从展开的多肽链到最终折叠构象的途径。 对于这样的理解，使用基于物理学的方法，即仅基于势能函数的全局优化的方法（包括溶剂的作用），而不使用二级结构预测，同源建模，线程等这种方法需要一个可靠的潜在功能和有效的程序全局优化;本计画系关于发展及改良所需之经验势函数。 最初，使用联合残基（UNRES）势函数。 UNRES将通过晶体计算得到改进，包括熵。 然后，通过对包含水合作用的全原子势函数进行Z分数优化，将改进的UNRES势函数转换为全原子处理。 UNRES潜在的功能正在改善生成诱饵与朗之万动力学和纳入熵的努力，使用分层优化程序。 全原子势函数（包括广义玻恩溶剂化模型）将通过用于改进UNRES势函数的相同分层优化程序来改进。 搜索过程将通过改进构象空间退火（CSA）方法来进行。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作用的基本理解，并将提供培训，不仅为进行这项研究的两名同事，而且还为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（当小组成员参加纽约州各学校8年级和9年级学生的外展职业探索时），小组的研究生和博士后成员将参加康奈尔大学为小学生开设的数学、科学和工程专业的拓展视野项目。

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.