Coleman Ryan G, Sharp Kim A
The Johnson Research Foundation, Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA.
J Mol Biol. 2006 Sep 22;362(3):441-58. doi: 10.1016/j.jmb.2006.07.022. Epub 2006 Jul 15.
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.
深度是一个经常应用于大分子形状和表面的术语，例如用于描述DNA中的凹槽、酶活性位点的形状或蛋白质中小分子的结合位点。然而，在大分子中严格定义深度是一项困难的属性，并且几乎没有计算工具可用于量化这一概念、将其可视化或分析结果。我们提出了行程深度的概念，简单来说，就是溶剂分子从表面点到适当定义的参考表面必须行进的物理距离。为了定义参考表面，我们使用随着探针尺寸增加的分子表面的极限形式：凸包。然后，我们提出了一种快速、稳健的近似算法来计算到每个表面点的行程深度。行程深度很有用，因为它适用于任何大小和复杂度的口袋。它也适用于两种有趣的特殊情况。第一，它适用于DNA中的凹槽，这些凹槽在一个方向上是无界的。第二，它适用于隧道的情况，即没有“底部”但贯穿整个大分子的口袋。我们的算法使得在分析结构时量化深度讨论变得很直接。我们的算法还实现了对大分子深度的高通量分析。通过分析蛋白质 - 小分子结合口袋数据库以及RNA结构中结合镁离子的分布来证明这一点。这些分析显示了深度对配体结合定位和强度有显著但微妙的影响。
