Conformer selection and induced fit in flexible backbone protein-protein docking using computational and NMR ensembles
Conformer selection and induced fit in flexible backbone protein-protein docking using computational and NMR ensembles
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DOI：
10.1016/j.jmb.2008.05.042
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发表时间：
2008-09-12
影响因子：
5.6
通讯作者：
Gray, Jeffrey J.
中科院分区：
文献类型：
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作者：
Chaudhury, Sidhartha;Gray, Jeffrey J.
骨架柔性的增强一直是蛋白质-蛋白质复合物计算对接中最困难的挑战。为此，我们模拟四个不同的生物物理模型的蛋白质结合RosettaDock，多尺度的蒙特-卡罗为基础的算法，使用准动力学搜索过程来模拟两种蛋白质的扩散遇到，并确定低能量的复合物。四种结合模型如下：（1）键锁（KL）模型，使用刚性骨架对接;（2）构象选择（CS）模型，使用新的系综对接算法;（3）诱导拟合（IF）模型，使用基于能量梯度的骨架最小化;和（4）组合构象选择/诱导拟合（CS/IF）模型。骨架的灵活性被限制在较小的合作伙伴的复杂，结构合奏使用Rosetta精化方法产生，和对接组成的局部扰动周围的复杂的构象使用未绑定的组件晶体结构的一组21个目标复合物。对于KL、CS、IF和CS/IF对接的9、13、13和14个靶标，最低能量结构分别含有> 30%的天然残基-残基接触。当应用于15个目标使用核磁共振合奏的较小的蛋白质，最低能量的结构恢复至少30%的天然残基接触，分别在3，8，4和8个目标KL，CS，IF，CS/IF对接。在15例中的10例中，核磁共振系综的CS/IF对接与KL与未结合晶体结构的对接同样好或更好。CS和CS/IF对接的显著成功表明，系综对接可以是一个通用的和有效的方法，以适应对接中的构象可塑性，并作为CS理论的示范，即结合能力的构象存在于未结合的系综，并可以选择基于其有利的结合能。(C)2008爱思唯尔有限公司保留所有权利。
Accommodating backbone flexibility continues to be the most difficult challenge in computational docking of protein-protein complexes. Towards that end, we simulate four distinct biophysical models of protein binding in RosettaDock, a multiscale Monte-Carlo-based algorithm that uses a quasi-kinetic search process to emulate the diffusional encounter of two proteins and to identify low-energy complexes. The four binding models are as follows: (1) key-lock (KL) model, using rigid-backbone docking; (2) conformer selection (CS) model, using a novel ensemble docking algorithm; (3) induced fit (IF) model, using energy-gradient-based backbone minimization; and (4) combined conformer selection/induced fit (CS/IF) model. Backbone flexibility was limited to the smaller partner of the complex, structural ensembles were generated using Rosetta refinement methods, and docking consisted of local perturbations around the complexed conformation using unbound component crystal structures for a set of 21 target complexes. The lowest-energy structure contained >30% of the native residue-residue contacts for 9, 13, 13, and 14 targets for KL, CS, IF, and CS/IF docking, respectively. When applied to 15 targets using nuclear magnetic resonance ensembles of the smaller protein, the lowest-energy structure recovered at least 30% native residue contacts in 3, 8, 4, and 8 targets for KL, CS, IF, and CS/IF docking, respectively. CS/IF docking of the nuclear magnetic resonance ensemble performed equally well or better than KL docking with the unbound crystal structure in 10 of 15 cases. The marked success of CS and CS/IF docking shows that ensemble docking can be a versatile and effective method for accommodating conformational plasticity in docking and serves as a demonstration for the CS theory-that binding-competent conformers exist in the unbound ensemble and can be selected based on their favorable binding energies. (C) 2008 Elsevier Ltd. All rights reserved.