Discrimination of near-native structures in protein-protein docking by testing the stability of local minima
Discrimination of near-native structures in protein-protein docking by testing the stability of local minima
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DOI：
10.1002/prot.21997
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发表时间：
2008-08-15
影响因子：
2.9
通讯作者：
Vajda, Sandor
中科院分区：
文献类型：
--
作者：
Kozakov, Dima;Schueler-Furman, Ora;Vajda, Sandor
蛋白质-蛋白质对接的快速傅立叶变换(FFT)相关方法，结合低能构象聚类，可以在能量面上找到多个局部极小点。对于大多数复合体，近自然结构的位置可以被限制在30个最大的簇，每个簇围绕着一个局部最小值。然而，由于极小值之间的能级差异与能量评估中的误差相当，因此不能通过能量测量获得可靠的进一步区分。事实上，没有当前的评分函数来解释与极小值宽度有关的熵贡献，而不是与其深度有关的熵贡献。由于处于窄极小值的结构释放了更多的熵，通过确定局部极小值是否被能量表面上的大吸引区包围，可以检测到一些非本征态。分析的基础是从每个最小值周围的随机点开始运行蒙特卡罗最小化(MCM)，并观察一定比例的轨迹是否收敛到集群内的一个小区域。如果存在这样的强吸引子，至少有10个收敛轨迹，相对接近原始星系团中心，并包含低能量结构，则认为该星系团是稳定的。我们在蛋白质对接基准中研究了酶抑制剂和抗体-抗原复合体的簇的稳定性。分析产生了三个主要结果。首先，所有接近本征结构的团簇都是稳定的。其次，将考虑因素限制在稳定的星团可以消除大约一半的假阳性，也就是说，解决方案的能量低，但远离复杂的自然结构。第三，将构象空间分成簇，并确定每个簇的稳定性，与蒙特卡罗极小化方法相比，该方法对先验信息的依赖程度更低。
Fast Fourier transform (FFT) correlation methods of protein-protein docking, combined with the clustering of low energy conformations, can find a number of local minima on the energy surface. For most complexes, the locations of the near-native structures can be constrained to the 30 largest clusters, each surrounding a local minimum. However, no reliable further discrimination can be obtained by energy measures because the differences in the energy levels between the minima are comparable with the errors in the energy evaluation. In fact, no current scoring function accounts for the entropic contributions that relate to the width rather than the depth of the minima. Since structures at narrow minima loose more entropy, some of the nonnative states can be detected by determining whether or not a local minimum is surrounded by a broad region of attraction on the energy surface. The analysis is based on starting Monte Carlo Minimization (MCM) runs from random points around each minimum, and observing whether a certain fraction of trajectories converge to a small region within the cluster. The cluster is considered stable if such a strong attractor exists, has at least 10 convergent trajectories, is relatively close to the original cluster center, and contains a low energy structure. We studied the stability of clusters for enzyme-inhibitor and antibody-antigen complexes in the Protein Docking Benchmark. The analysis yields three main results. First, all clusters that are close to the native structure are stable. Second, restricting considerations to stable clusters eliminates around half of the false positives, that is, solutions that are low in energy but far from the native structure of the complex. Third, dividing the conformational space into clusters and determining the stability of each cluster, the combined approach is less dependent on a priori information than exploring the potential conformational space by Monte Carlo minimizations.