Department of Biochemistry and Molecular Biophysics, Center for Computational Biology and Bioinformatics, Columbia University, New York, New York, United States of America.
PLoS Comput Biol. 2010 Aug 12;6(8):e1000881. doi: 10.1371/journal.pcbi.1000881.
Many algorithms that compare protein structures can reveal similarities that suggest related biological functions, even at great evolutionary distances. Proteins with related function often exhibit differences in binding specificity, but few algorithms identify structural variations that effect specificity. To address this problem, we describe the Volumetric Analysis of Surface Properties (VASP), a novel volumetric analysis tool for the comparison of binding sites in aligned protein structures. VASP uses solid volumes to represent protein shape and the shape of surface cavities, clefts and tunnels that are defined with other methods. Our approach, inspired by techniques from constructive solid geometry, enables the isolation of volumetrically conserved and variable regions within three dimensionally superposed volumes. We applied VASP to compute a comparative volumetric analysis of the ligand binding sites formed by members of the steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domains and the serine proteases. Within both families, VASP isolated individual amino acids that create structural differences between ligand binding cavities that are known to influence differences in binding specificity. Also, VASP isolated cavity subregions that differ between ligand binding cavities which are essential for differences in binding specificity. As such, VASP should prove a valuable tool in the study of protein-ligand binding specificity.
许多比较蛋白质结构的算法可以揭示出相似性，从而提示相关的生物功能，即使在很大的进化距离上也是如此。具有相关功能的蛋白质通常在结合特异性上表现出差异，但很少有算法能识别出影响特异性的结构变化。为了解决这个问题，我们描述了一种新的体积分析工具——表面性质体积分析（VASP），用于比较对齐的蛋白质结构中的结合位点。VASP 使用实心体积来表示蛋白质形状和用其他方法定义的表面腔、裂隙和隧道的形状。我们的方法受构造立体几何技术的启发，能够在三维重叠的体积内分离出体积上保守和可变的区域。我们应用 VASP 对类固醇生成急性调节蛋白（StAR）相关脂质转移（START）结构域和丝氨酸蛋白酶成员形成的配体结合位点进行了比较体积分析。在这两个家族中，VASP 分离出了在已知影响结合特异性差异的配体结合腔之间产生结构差异的单个氨基酸。此外，VASP 还分离出了配体结合腔之间的腔亚区，这些亚区对于结合特异性的差异至关重要。因此，VASP 应该成为研究蛋白质-配体结合特异性的有用工具。
