ITR: A Protocol For Computational Protein Design

该奖项是根据ITR招标NSF-02-168提交的“小型”类别提案而颁发的。它支持蛋白质折叠和设计的计算研究。PI的目的是提供一个全面的计算协议，利用可设计性的原则，以解决设计新的蛋白质折叠的基本问题。将在算法上进行改进，以提高协议中主链选择的模数。研究将解决从骨架建模到结构筛选和聚类到可设计性的随机计算等问题，以获得比以前认为可能的更长的蛋白质的新骨架构象的最佳策略。一个高分辨率的全原子模型将被用来包装合适的选择的侧链到骨干，以获得现实的蛋白质构象的实验验证。其中包括：（1）更精确的溶剂化能函数的两两分解;（2）改进广泛使用的侧链填充方法，以显著提高嵌入随机抽样方案的确定性死端消除算法的计算速度;以及（3）一种新的参数化方案来表征蛋白质结构的二级结构元件的灵活性，以克服目前大多数现有算法所施加的固定骨架方法的严重限制。该奖项还支持研究生和博士后水平的教育，并提供工业实验室的研究经验。%此奖项是根据ITR招标NSF-02-168提交的“小型”类别提案授予的。它支持多学科的计算研究，涉及统计力学，分子生物物理学和计算机科学的蛋白质折叠和设计。 虽然在自然界中观察到的许多蛋白质中存在氨基酸序列的巨大多样性，仅在人体中就有大约10万种不同的蛋白质，但结构的多样性要有限得多。据估计，自然界中只有大约1000种不同的蛋白质折叠。 PI试图开发一种基于“可设计性原则”的设计新蛋白质折叠的方法。由PI开发的可设计性原则将高度可设计的结构和高度稳定的氨基酸序列联系起来。研究涉及实现和改进计算算法。通过在所提出的方案的不同阶段对各种选项、标准和算法进行集中和有条理的检查，PI的目标是设计一个强大而实用的计算机蛋白质设计工具。该奖项还支持研究生和博士后水平的教育，并提供工业实验室的研究经验。***

This award was made on a 'small' category proposal submitted in response to the ITR solicitation, NSF-02-168. It supports computational research on protein folding and design. The PIs aim to provide a comprehensive computational protocol utilizing the principle of designability in order to address the fundamental problem of designing novel protein folds. Algorithmic improvements will be made to enhance the modulus on backbone selection in the protocol. Research will address issues ranging from backbone modeling to structure screening and clustering to stochastic computation of designability to obtain an optimal strategy in the search for novel backbone conformations of much longer proteins than previously thought possible. A high-resolution all-atomic modeling will be employed to pack suitable choices of side-chains onto the backbone to obtain realistic protein conformations for experimental verification. New elements that will be actively explored, include: (1) a more accurate pairwise decomposition of the solvation energy function; (2) improving a widely used method of side-chain packing to obtain a significant increase of computational speed for the deterministic dead-end-elimination algorithm with stochastic sampling schemes embedded; and (3) a novel parametric scheme to characterize the flexibilities of secondary structure elements of a protein structure to overcome the severe limitation of the fixed-backbone methodology imposed by most of currently existing algorithms. This award also supports education at the graduate and postdoctoral level and provides research experience in an industrial laboratory. %%%This award was made on a 'small' category proposal submitted in response to the ITR solicitation, NSF-02-168. It supports multidisciplinary computational research involving statistical mechanics, molecular biophysics and computer science on protein folding and design. While there is a great diversity of amino acid sequences in the many proteins observed in nature, about 100,000 different proteins in the human body alone, the diversity of structures is much more limited. It is estimated that there are only about 1000 distinct protein folds in nature. The PIs seek to develop a method for designing novel protein folds that is based on the "designability principle." The designability principle, developed by the PIs, connects highly designable structures and highly stable amino-acid sequences. Research involves implementing and improving computational algorithms. By a focused and methodical examination of various options, criteria, and algorithms at the different stages of the proposed protocol, the PIs aim to design a powerful and practical tool for protein design by computer. This award also supports education at the graduate and postdoctoral level and provides research experience in an industrial laboratory. ***