Thermodynamic perspective on the dock-lock growth mechanism of amyloid fibrils.
Thermodynamic perspective on the dock-lock growth mechanism of amyloid fibrils.
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DOI：
10.1021/jp9050098
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发表时间：
2009-10-29
期刊：
影响因子：
--
通讯作者：
Thirumalai D
中科院分区：
文献类型：
--
作者：
O'Brien EP;Okamoto Y;Straub JE;Brooks BR;Thirumalai D
将可溶性非结构化单体添加到预先形成的有序淀粉样蛋白原纤维中的机制是一个复杂的过程。基于Aβ（1 - 40）从淀粉样蛋白原纤维上单体解离的动力学，已经表明沉积是一个多步骤过程，涉及非结构化单体与原纤维表面的快速可逆缔合（对接），随后是较慢的构象重排，导致掺入到下面的原纤维晶格上（锁定）。通过利用对接和锁定过程之间的巨大时间尺度分离，并使用分子动力学模拟无序肽片段35 MVGGVV 40从Aβ肽沉积到具有已知晶体结构的原纤维上，我们为原纤维生长的对接锁定机制提供了热力学基础。使用隐式溶剂模型和增强采样方法计算的自由能分布，以肽的质心与原纤维表面之间的距离（δC）作为序参量，显示出三个不同的吸引盆地。当δC很大时，单体是紧密的和非结构化的，并且与原纤维的有利相互作用导致肽在δC为13 π时的拉伸。随着δC进一步降低，肽停靠在原纤维表面上，其结构由肽内和肽原纤维相互作用之间的平衡决定。在δC = 40时，与原纤维中β链之间的间距相当的值，单体膨胀并锁定在原纤维上。使用模拟与隐式溶剂模型和所有的原子分子动力学在明确的水，我们表明，锁定的单体，与底层的原纤维相互作用，经历了大量的构象波动，是不稳定的。共溶质尿素和TMAO使未结合相不稳定并使对接相稳定。有趣的是，小的拥挤颗粒只能略微提高原纤维结合单体的稳定性。我们预测，实验可测量的临界单体浓度，CR，在其中的可溶性未结合的单体是在与有序的原纤维平衡，急剧增加，在所有的溶液条件下，随着温度的增加。
The mechanism of addition of a soluble unstructured monomer to a preformed ordered amyloid fibril is a complex process. Based on the kinetics of monomer disassociation of Aβ(1 — 40) from the amyloid fibril, it has been suggested that deposition is a multi-step process involving a rapid reversible association of the unstructured monomer to the fibril surface (docking) followed by a slower conformational rearrangement leading to the incorporation onto the underlying fibril lattice (locking). By exploiting the vast time scale separation between the dock and lock processes and using molecular dynamics simulation of deposition of the disordered peptide fragment 35MVGGVV40, from the Aβ peptide, onto the fibril with known crystal structure we provide a thermodynamic basis for the dock-lock mechanism of fibril growth. Free energy profiles, computed using implicit solvent model and enhanced sampling methods, with the distance (δC) between the center of mass of the peptide and the fibril surface as the order parameter, show three distinct basins of attraction. When δC is large the monomer is compact and unstructured, and the favorable interactions with the fibril results in stretching of the peptide at δC ≈ 13 Å. As δC is further decreased the peptide docks onto the fibril surface with a structure that is determined by a balance between intrapeptide and peptide fibril interactions. At δC ≈ 4 Å, a value that is commensurate with the spacing between β-strands in the fibril, the monomer expands and locks onto the fibril. Using simulations with implicit solvent model and all atom molecular dynamics in explicit water, we show that the locked monomer, which interacts with the underlying fibril, undergoes substantial conformational fluctuations and is not stable. The cosolutes urea and TMAO destabilize the unbound phase and stabilize the docked phase. Interestingly, small crowding particles enhance the stability of the fibril-bound monomer only marginally. We predict that the experimentally-measurable critical monomer concentration, CR, at which the soluble unbound monomer is in equilibrium with the ordered fibril, increases sharply as temperature is increased under all solution conditions.
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影响因子：
9.8
作者：
Collins SR;Douglass A;Vale RD;Weissman JS
通讯作者：
Weissman JS
影响因子：
2.9
作者：
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通讯作者：
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DOI：
10.1002/prot.340230412
发表时间：
1995-12-01
期刊：
PROTEINS-STRUCTURE FUNCTION AND GENETICS
影响因子：
--
作者：
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通讯作者：
Argos, P
影响因子：
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作者：
Auer, Stefan;Dobson, Christopher M.;Vendruscolo, Michele
通讯作者：
Vendruscolo, Michele
影响因子：
4.4
作者：
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通讯作者：
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