A Free-Energy Landscape for Coupled Folding and Binding of an Intrinsically Disordered Protein in Explicit Solvent from Detailed All-Atom Computations
A Free-Energy Landscape for Coupled Folding and Binding of an Intrinsically Disordered Protein in Explicit Solvent from Detailed All-Atom Computations
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DOI：
10.1021/ja110338e
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发表时间：
2011-07-13
影响因子：
15
通讯作者：
Nakamura, Haruki
中科院分区：
文献类型：
--
作者：
Higo, Junichi;Nishimura, Yoshifumi;Nakamura, Haruki
神经限制性沉默因子（NRSF）的N-末端阻遏物结构域是一种与成对的两亲性螺旋（PAH）结合的内在无序蛋白（IDP）。msin 3的结构域。NMR实验显示，NRSF的最小结合单元是15个残基的片段，其在与mSin 3的裂缝结合时采用螺旋结构。我们计算了该系统的自由能景观的增强构象采样方法，全原子多正则分子动力学。模拟从NRSF片段完全无序且远离明确溶剂中的mSin 3的构型开始。在没有mSin 3的情况下，无序的NRSF片段在发夹、螺旋和弯曲结构之间热波动。在mSin 3的存在下，通过采用在分离状态中涉及的结构而结合到mSin 3的片段，并且形成非天然和天然复合物。自由能景观由三个超星系团组成，自由能屏障将超星系团分开。天然复合物位于最低自由能簇的中心。当NRSF降落在最大的超星系团中时，产生的非原生复合物通过增加界面疏水接触和螺旋含量而在景观上移动以折叠成原生复合物。当NRSF降落在其他超星系团中时，非原生复合物克服了mSin 3结合裂缝中各个片段方向之间的自由能障碍。群体迁移和诱导契合（或诱导折叠）机制在耦合折叠和结合中协同工作。NRSF的多样结构适应性可能与IDP的枢纽特性有关。
The N-terminal repressor domain of neural restrictive silencer factor (NRSF) is an intrinsically disordered protein (IDP) that binds to the paired amphipathic helix (PAH.) domain of mSin3. An NMR experiment revealed that the minimal binding unit of NRSF is a 15-residue segment that adopts a helical structure upon binding to a cleft of mSin3. We computed a free-energy landscape of this system by an enhanced conformational sampling method, all-atom multicanonical molecular dynamics. The simulation started from a configuration where the NRSF segment was fully disordered and distant from mSin3 in explicit solvent. In the absence of mSin3, the disordered NRSF segment thermally fluctuated between hairpins, helices, and bent structures. In the presence of mSin3, the segment bound to mSin3 by adopting the structures involved in the isolated state, and non-native and native complexes were formed. The free-energy landscape comprised three superclusters, and free-energy barriers separated the superclusters. The native complex was located at the center of the lowest free-energy cluster. When NRSF landed in the largest supercluster, the generated non-native complex moved on the landscape to fold into the native complex, by increasing the interfacial hydrophobic contacts and the helix content. When NRSF landed in other superclusters, the non-native complex overcame the free-energy barriers between the various segment orientations in the binding cleft of mSin3. Both population-shift and induced-fit (or induced-folding) mechanisms work cooperatively in the coupled folding and binding. The diverse structural adaptability of NRSF may be related to the hub properties of the IDP.