Long-Range Conformational Response of a PDZ Domain to Ligand Binding and Release: A Molecular Dynamics Study.
Long-Range Conformational Response of a PDZ Domain to Ligand Binding and Release: A Molecular Dynamics Study.
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PDZ 结构域对配体结合和释放的长程构象响应：分子动力学研究
DOI：
10.1021/acs.jctc.5b01009
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发表时间：
2015
影响因子：
5.5
通讯作者：
G. Stock
中科院分区：
文献类型：
--
作者：
V. Knecht;G. Stock
配体与蛋白质的结合可以诱导生物大分子中的长程结构或动力学变化，即使在与结合口袋物理上良好分离的位点处也是如此。已经广泛讨论了这种行为的系统是人酪氨酸磷酸酶1 E的PDZ 2结构域。在这里，我们提出的结果从平衡轨迹的PDZ 2域在自由和配体结合状态，以及非平衡模拟的松弛PDZ 2后，去除其肽配体。该研究揭示了配体释放后残基间接触、骨架二面角和Cα位置的变化。我们的研究结果显示PDZ 2结构域对配体释放的长程构象反应，其形式为二级结构元件α2、β2、β3、α1-β4和C末端环相对于蛋白质的其余部分远离N末端的集体移位，以及环β2-β 3和β1-β 2在相反方向的移位。这些位移导致主链构象的变化，尤其是β2-β 3环，但也包括β5-α 2和α2-β 6环，并伴随着主要在β2-β 3环内以及α 2螺旋与其他片段之间残基间接触的变化。显示残基间接触、主链构象或Cα位置的实质性变化的残基被认为是PDZ 2的长程构象响应的“关键残基”。通过比较这些残基与以前的研究PDZ 2突出显示的各种残基，我们研究了各种方法的统计相关性。有趣的是，我们发现我们的研究结果与考虑结构变化的几个工程有相当大的相关性，但与考虑能量流或基于残基间能量的网络的方法没有显着的相关性。
The binding of a ligand to a protein may induce long-range structural or dynamical changes in the biomacromolecule even at sites physically well separated from the binding pocket. A system for which such behavior has been widely discussed is the PDZ2 domain of human tyrosine phosphatase 1E. Here, we present results from equilibrium trajectories of the PDZ2 domain in the free and ligand-bound state, as well as nonequilibrium simulations of the relaxation of PDZ2 after removal of its peptide ligand. The study reveals changes in inter-residue contacts, backbone dihedral angles, and Cαpositions upon ligand release. Our findings show a long-range conformational response of the PDZ2 domain to ligand release in the form of a collective shift of the secondary structure elements α2, β2, β3, α1-β4, and the C terminal loop relative to the rest of the protein away from the N-terminus, and a shift of the loops β2-β3and β1-β2in the opposite direction. The shifts lead to conformational changes in the backbone, especially in the β2-β3loop but also in the β5-α2and the α2-β6loop, and are accompanied by changes of inter-residue contacts mainly within the β2-β3loop as well as between the α2helix and other segments. The residues showing substantial changes of inter-residue contacts, backbone conformations, or Cαpositions are considered “key residues” for the long-range conformational response of PDZ2. By comparing these residues with various sets of residues highlighted by previous studies of PDZ2, we investigate the statistical correlation of the various approaches. Interestingly, we find a considerable correlation of our findings with several works considering structural changes but no significant correlations with approaches considering energy flow or networks based on inter-residue energies.
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