Representation of Flexible Biomolecular Shapes

描述(由申请人提供)：分子柔性是生物分子的固有属性，通常是其功能所必需的。它的理解对于将结构与生物功能联系起来非常重要，生物功能是计算机辅助药物设计的核心。缺乏高水平的分子灵活性表示，阻碍了目前的模拟方法能够预测呈现药物诱导的受体构象变化的复合体。该项目提出了一种新的基于分层树状结构的分子灵活性多分辨率编码的开发。该灵活性树(FT)中的每个节点将代表原子的子集，这些原子在给定的近似级别下作为刚体移动。每个节点将存储有关其子节点运动的信息。分配给子节点的形状将用于递归定义父节点的形状。将开发用于形状和运动的卷积以及用于评估该树所描述的构象的适合性的算子。对接程序AutoDock将使用FT扩展到表示蛋白质的灵活性。这种数据结构将使得：1)在计算模型中将大分子柔性的高级表示为在不同尺度上发生的嵌套运动的组合，2)对感兴趣的构象子空间进行选择性编码，以及3)研究柔性对分子形状和性质的影响。这项拟议的研究为结构分子生物学家定义了一个新的框架，使用形状和柔性信息的统一、多尺度表示来分析分子结构及其相互作用。它将有助于增加我们对生物分子灵活性的基本性质的理解，并为将蛋白质灵活性集成到计算方法中提供基础设施，如自动对接。它还将提供计算工具，以交互或编程方式探索不同细节水平的分子灵活性。这些工具将在大量计算平台上提供给科学界，以确保它们得到广泛传播。这些工具有望极大地扩展可以成功模拟的生物系统的范围，从而提高我们发现和优化新药的能力。

DESCRIPTION (provided by applicant): Molecular flexibility is an intrinsic property of bio-molecules and is often essential for their function. Its understanding is important for relating structure to biological function, which is at the heart of computer aided drug design. The lack of high-level representation of molecular flexibility prevents current simulation methods from being able to predict complexes presenting drug-induced conformational changes in the receptor. This project proposes the development of a novel multiresolution encoding of molecular flexibility, based on a hierarchical, tree-like structure. Each node in this Flexibility Tree (FT) will represent a subset of atoms that move as a rigid body at a given level of approximation. Every node will store information about the motion of its children. Shapes assigned to child nodes will be used to define recursively the shape of parent nodes. Operators for the convolution of shape and motion, and for the evaluation of the fitness of conformations described by this tree will be developed. The docking program AutoDock will be extended to represent protein flexibility using the FT. This data structure will enable: 1) the high-level representation in computational models of macro- molecular flexibility as a combination of nested motions occurring at different scales, 2) the selective encoding of a conformational sub-space of interest, and 3) the study of the effects of flexibility on molecular shape and properties. The proposed research defines a novel framework for structural molecular biologists to analyze molecular structures and their interactions using a unified, multi-scale representation of both shape and flexibility information. It will help increase our understanding of the fundamental nature of biomolecular flexibility and provide the infrastructure for integrating protein flexibility in computational methods such as automated docking. It will also provide computational tools to explore, either interactively or programmatically, molecular flexibility at various levels of detail. These tools will be made available to the scientific community on a large number of computational platforms to ensure their wide dissemination. These tools hold the promise of extending dramatically the range of biological systems that can be simulated successfully, and thereby improve our ability to discover and optimize new drugs.