Rigidity and flexibility of large bio-molecular assemblies

描述(申请人提供)：生物大分子(如蛋白质)是通过各种稳定作用结合在一起的柔性结构。这一提议的目的是促进我们对大分子集合体的三维结构和动力学与其生物功能的关系的理解。 我们建议对基于刚性的方法进行系统的(数学、算法和生物学)研究，以模拟生物分子的慢动作构象变化。将大分子分解成刚性团簇导致结构的自由度要少得多。我们将它们视为运动学连杆，即通过各种类型的柔性关节相互连接的关节刚体的集合。我们将在这些运动学抽象的基础上开发新的运动模拟方法。这种方法的本质是对构象空间进行实质性降维。 为了测试和实验我们的想法，我们将开发新的软件来生成生物大分子的运动学逼真运动，该软件建立在最近发布的软件基础设施Kinari(http://kinari.cs.umass.edu))的基础上，并集成到最近发布的软件基础设施Kinari中。我们将对我们的模型和新方法进行评估和基准测试，以获得准确性和速度，并与其他粗粒度模型(如正常模式分析)进行比较，并将在生物数据上验证它们。 数学和计算的方法是发展一种严格的分子结构变形理论，将分子结构建模为关节实体系统，观察其基本构型空间的拓扑结构，并通过基本运动学约束指导的运动产生有效的模拟技术。 这项研究有望增强对蛋白质灵活性和变构的总体理解，影响使用低分辨率实验数据确定蛋白质结构的方案，并最终基于对蛋白质与灵活性和运动相关的功能的更好理解，为新药的合理设计提供信息。

DESCRIPTION (provided by applicant): Biological macromolecules (such as proteins) are flexible structures held together by a variety of stabilizing interactions. The aim of this proposa is to advance our understanding of how the three-dimensional structure and dynamics of large molecular assemblies relate to their biological functions. We propose a systematic (mathematical, algorithmic and biological) study of rigidity-based methods for simulating slow-motion conformational changes in biomolecules. Decomposing large molecules into rigid clusters leads to structures with a much smaller number of degrees of freedom. We treat them as kinematic linkages, i.e. as collections of articulated rigid bodies interconnected through various types of flexible joints. We will develop new methods for motion simulation, based on these kinematic abstractions. The essence of this approach is a substantial dimensionality reduction of the conformational space. To test and experiment with our ideas, we will develop new software for generating kinematically-realistic motions of biological macromolecules, built upon and integrated into the recently released software infrastructure KINARI (http://kinari.cs.umass.edu) developed in PI Streinu's group. We will evaluate and benchmark our models and our new methods, for accuracy and speed, against other coarse-grained models (such as Normal Mode Analysis) and will validate them on biological data. The mathematical and computational approach is to develop a rigorous deformation theory for molecular structures modeled as systems of articulated bodies, observant of the topology of their underlying configuration spaces and leading to effective simulation techniques through motions that are guided by essential kinematic constraints. This research is anticipated to enhance the general understanding of flexibility and allostery in proteins, to impact protocols for protein structure determination using low-resolution experimental data and, ultimately, to inform the rational design of new drugs based on improved understanding of protein functions as they relate to flexibility and motion.