Rigidity and flexibility of large bio-molecular assemblies

描述（由申请人提供）：生物大分子（如蛋白质）是通过各种稳定相互作用保持在一起的柔性结构。这个命题的目的是推进我们对大分子组装体的三维结构和动力学与其生物学功能的关系的理解。 我们提出了一个系统的（数学，算法和生物）的刚性为基础的方法模拟慢动作的生物分子的构象变化的研究。将大分子分解成刚性簇会导致结构具有更少的自由度。我们把它们作为运动学联系，即作为通过各种类型的柔性关节相互连接的铰接刚体的集合。我们将开发新的运动模拟方法，这些运动学抽象的基础上。这种方法的本质是构象空间的大幅降维。 为了测试和实验我们的想法，我们将开发新的软件，用于生成生物大分子的运动学逼真的运动，建立在PI Streinu小组开发的最近发布的软件基础设施KINARI（http：//www.example.com）上并集成到其中。kinari.cs.umass.edu我们将评估和基准测试我们的模型和我们的新方法，针对其他粗粒度模型（如正态模式分析）的准确性和速度，并将在生物数据上验证它们。 数学和计算方法是发展一个严格的变形理论的分子结构建模为系统的关节机构，观察其底层的配置空间的拓扑结构，并导致有效的模拟技术，通过运动的指导下，基本的运动学约束。 这项研究预计将增强对蛋白质灵活性和变构性的一般理解，影响使用低分辨率实验数据确定蛋白质结构的方案，并最终为基于对蛋白质功能的更好理解的新药的合理设计提供信息，因为它们与灵活性和运动有关。

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.