Lin Ming, Lu Hsiao-Mei, Chen Rong, Liang Jie
Department of Information and Decision Science, University of Illinois at Chicago, 845 S. Morgan St., Chicago, Illinois 60607, USA.
J Chem Phys. 2008 Sep 7;129(9):094101. doi: 10.1063/1.2968605.
Inferring three-dimensional structural information of biomacromolecules such as proteins from limited experimental data is an important and challenging task. Nuclear Overhauser effect measurements based on nucleic magnetic resonance, disulfide linking, and electron paramagnetic resonance labeling studies can all provide useful partial distance constraint characteristic of the conformations of proteins. In this study, we describe a general approach for reconstructing conformations of biomolecules that are consistent with given distance constraints. Such constraints can be in the form of upper bounds and lower bounds of distances between residue pairs, contact maps based on specific contact distance cutoff values, or indirect distance constraints such as experimental phi-value measurement. Our approach is based on the framework of sequential Monte Carlo method, a chain growth-based method. We have developed a novel growth potential function to guide the generation of conformations that satisfy given distance constraints. This potential function incorporates not only the distance information of current residue during growth but also the distance information of future residues by introducing global distance upper bounds between residue pairs and the placement of reference points. To obtain protein conformations from indirect distance constraints in the form of experimental phi-values, we first generate properly weighted contact maps satisfying phi-value constraints, we then generate conformations from these contact maps. We show that our approach can faithfully generate conformations that satisfy the given constraints, which approach the native structures when distance constraints for all residue pairs are given.
从有限的实验数据推断蛋白质等生物大分子的三维结构信息是一项重要且具有挑战性的任务。基于核磁共振的核Overhauser效应测量、二硫键连接以及电子顺磁共振标记研究都能提供有关蛋白质构象的有用的部分距离约束特征。在本研究中，我们描述了一种用于重建与给定距离约束一致的生物分子构象的通用方法。此类约束可以是残基对之间距离的上限和下限、基于特定接触距离截止值的接触图，或者诸如实验phi值测量等间接距离约束的形式。我们的方法基于序贯蒙特卡罗方法的框架，这是一种基于链增长的方法。我们开发了一种新颖的增长势函数来指导满足给定距离约束的构象的生成。该势函数不仅纳入了生长过程中当前残基的距离信息，还通过引入残基对之间的全局距离上限和参考点的放置纳入了未来残基的距离信息。为了从实验phi值形式的间接距离约束中获得蛋白质构象，我们首先生成满足phi值约束的适当加权的接触图，然后从这些接触图生成构象。我们表明，我们的方法能够忠实地生成满足给定约束的构象，当给出所有残基对的距离约束时，这些构象接近天然结构。
