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特性，通常对其功能至关重要。它的理解对于将结构与生物功能联系起来非常重要，这是计算机辅助药物设计的核心。缺乏高层次的分子灵活性的代表性，防止目前的模拟方法能够预测复合物呈现药物诱导的受体构象变化。该项目提出了一种新的多分辨率编码的分子的灵活性，基于分层，树状结构的发展。这个柔性树（FT）中的每个节点将表示在给定近似水平下作为刚体移动的原子的子集。每个节点都将存储有关其子节点运动的信息。分配给子节点的指针将用于递归地定义父节点的形状。算子的卷积的形状和运动，并为评价的健身的构象所描述的这棵树将被开发。将扩展对接程序AutoDock以使用FT表示蛋白质柔性。该数据结构将使得：1）作为在不同尺度下发生的嵌套运动的组合的大分子柔性的计算模型中的高级表示成为可能，2）感兴趣的构象子空间的选择性编码，以及3）柔性对分子形状和性质的影响的研究。拟议的研究定义了一个新的框架，结构分子生物学家分析分子结构和它们的相互作用，使用统一的，多尺度的形状和灵活性的信息表示。它将有助于增加我们对生物分子柔性的基本性质的理解，并为在自动对接等计算方法中整合蛋白质柔性提供基础设施。它还将提供计算工具，以探索，无论是交互式或编程，分子的灵活性在不同层次的细节。这些工具将在大量计算平台上提供给科学界，以确保其广泛传播。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.