Travel depth, a new shape descriptor for macromolecules: Application to ligand binding
Travel depth, a new shape descriptor for macromolecules: Application to ligand binding
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DOI：
10.1016/j.jmb.2006.07.022
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发表时间：
2006-09-22
影响因子：
5.6
通讯作者：
Sharp, Kim A.
中科院分区：
文献类型：
--
作者：
Coleman, Ryan G.;Sharp, Kim A.
深度是一个经常用于描述大分子的形状和表面的术语，例如描述DNA中的沟槽、酶活性部位的形状或蛋白质中小分子的结合部位。然而，在大分子中，深度是一个很难严格定义的性质，而且几乎没有计算工具来量化这个概念，将其可视化，或分析结果。我们提出了行进深度的概念，简单地说就是溶剂分子必须从表面点行进到适当定义的参考面的物理距离。为了定义参考面，我们使用随探针尺寸增加的分子表面的极限形式：凸壳。然后，我们提出了一种快速、稳健的近似算法来计算到每个曲面点的旅行深度。旅行深度很有用，因为它适用于任何大小和复杂的口袋。它还适用于两个有趣的特殊情况。首先，它作用于DNA中的凹槽，这些凹槽在一个方向上是不受约束的。其次，它在隧道的情况下起作用，也就是说，隧道是没有“底部”的口袋，但要穿过整个大分子。我们的算法使得在分析结构时对深度的讨论变得简单明了。我们的算法还实现了高通量的大分子深度分析。这是通过分析蛋白质-小分子结合口袋的数据库和结合的镁离子在RNA结构中的分布来证明的。这些分析显示了深度对配体结合局部化和强度的显著但微妙的影响。(C)2006爱思唯尔有限公司。保留所有权利。
Depth is a term frequently applied to the shape and surface of macromolecules, describing for example the grooves in DNA, the shape of an enzyme active site, or the binding site for a small molecule in a protein. Yet depth is a difficult property to define rigorously in a macromolecule, and few computational tools exist to quantify this notion, to visualize it, or analyze the results. We present our notion of travel depth, simply put the physical distance a solvent molecule would have to travel from a surface point to a suitably defined reference surface. To define the reference surface, we use the limiting form of the molecular surface with increasing probe size: the convex hull. We then present a fast, robust approximation algorithm to compute travel depth to every surface point. The travel depth is useful because it works for pockets of any size and complexity. It also works for two interesting special cases. First, it works on the grooves in DNA, which are unbounded in one direction. Second, it works on the case of tunnels, that is pockets that have no "bottom", but go through the entire macromolecule. Our algorithm makes it straightforward to quantify discussions of depth when analyzing structures. High-throughput analysis of macromolecule depth is also enabled by our algorithm. This is demonstrated by analyzing a database of protein-small molecule binding pockets, and the distribution of bound magnesium ions in RNA structures. These analyses show significant, but subtle effects of depth on ligand binding localization and strength. (c) 2006 Elsevier Ltd. All rights reserved.