采样蛋白质表面残基的构象用于柔性蛋白质对接。

Sampling the conformation of protein surface residues for flexible protein docking.

机构信息

Department of Computer Science and Genome Center, University of California, Davis, CA 95616, USA.

出版信息

BMC Bioinformatics. 2010 Nov 23;11:575. doi: 10.1186/1471-2105-11-575.

DOI:10.1186/1471-2105-11-575

PMID:21092317

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3002368/

Abstract

BACKGROUND

The problem of determining the physical conformation of a protein dimer, given the structures of the two interacting proteins in their unbound state, is a difficult one. The location of the docking interface is determined largely by geometric complementarity, but finding complementary geometry is complicated by the flexibility of the backbone and side-chains of both proteins. We seek to generate candidates for docking that approximate the bound state well, even in cases where there is backbone and/or side-chain difference from unbound to bound states.

RESULTS

We divide the surfaces of each protein into local patches and describe the effect of side-chain flexibility on each patch by sampling the space of conformations of its side-chains. Likely positions of individual side-chains are given by a rotamer library; this library is used to derive a sample of possible mutual conformations within the patch. We enforce broad coverage of torsion space. We control the size of the sample by using energy criteria to eliminate unlikely configurations, and by clustering similar configurations, resulting in 50 candidates for a patch, a manageable number for docking.

CONCLUSIONS

Using a database of protein dimers for which the bound and unbound structures of the monomers are known, we show that from the unbound patch we are able to generate candidates for docking that approximate the bound structure. In patches where backbone change is small (within 1 Å RMSD of bound), we are able to account for flexibility and generate candidates that are good approximations of the bound state (82% are within 1 Å and 98% are within 1.4 Å RMSD of the bound conformation). We also find that even in cases of moderate backbone flexibility our candidates are able to capture some of the overall shape change. Overall, in 650 of 700 test patches we produce a candidate that is either within 1 Å RMSD of the bound conformation or is closer to the bound state than the unbound is.

摘要

背景

给定两个未结合状态下相互作用的蛋白质的结构，确定蛋白质二聚体的物理构象是一个难题。对接界面的位置主要由几何互补性决定，但由于两个蛋白质的骨架和侧链的灵活性，寻找互补的几何形状变得复杂。我们试图生成与结合状态非常接近的对接候选物，即使在与未结合状态相比骨架和/或侧链存在差异的情况下也是如此。

结果

我们将每个蛋白质的表面划分为局部斑块，并通过采样其侧链构象的空间来描述侧链灵活性对每个斑块的影响。单个侧链的可能位置由旋转体库给出；这个库被用来从斑块中推导出可能的相互构象的样本。我们强制广泛覆盖扭转空间。我们通过使用能量标准消除不太可能的构型，并通过聚类相似的构型来控制样本的大小，从而为斑块生成 50 个候选物，这是一个可管理的对接数量。

结论

使用单体的结合和未结合结构已知的蛋白质二聚体数据库，我们表明，从未结合的斑块中，我们能够生成与结合结构近似的对接候选物。在骨架变化较小的斑块中（与结合构象的 RMSD 为 1 Å 以内），我们能够考虑灵活性并生成与结合状态非常接近的候选物（82%在 1 Å 以内，98%在 1.4 Å RMSD 以内）。我们还发现，即使在中等骨架灵活性的情况下，我们的候选物也能够捕捉到一些整体形状变化。总的来说，在 700 个测试斑块中的 650 个中，我们生成了一个候选物，要么与结合构象的 RMSD 在 1 Å 以内，要么比未结合状态更接近结合状态。