Thermodynamics of amyloid dissociation provide insights into aggregate stability regimes
Thermodynamics of amyloid dissociation provide insights into aggregate stability regimes
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DOI：
10.1016/j.bpc.2012.06.001
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发表时间：
2012-07-01
影响因子：
3.8
通讯作者：
Roberts, Christopher J.
中科院分区：
文献类型：
--
作者：
Brummitt, Rebecca K.;Andrews, Jennifer M.;Roberts, Christopher J.
淀粉样蛋白聚集体被假设为有限浓度下蛋白质的全局低自由能状态。在接近其中点解折叠温度时，α-胰凝乳蛋白酶原A（aCgn）自发形成淀粉样蛋白聚合物，表明聚集体（A）的自由能在那些特定条件下显著低于解折叠（U）和天然（N）单体的自由能。通过量热法、尿素辅助展开和解离、聚集动力学和溶剂暴露表面积的变化，结合热力学积分和线性转移自由能模型，半定量地估计A、U和N状态的相对热力学稳定性作为温度（T）和[尿素]的函数。结果首先表明，在足够低的T和[尿素]下，N比A更稳定，但这可能与动力学效应有关。有趣的是，聚集体的动力学稳定性强调了稳定性的实际测量可能是A和U之间的自由能垒，因为U是N和A状态之间的关键中间体。(c)2012爱思唯尔有限公司版权所有。
Amyloid aggregates have been hypothesized as a global low free energy state for proteins at finite concentrations. Near its midpoint unfolding temperature, alpha-chymotrypsinogen A (aCgn) spontaneously forms amyloid polymers, indicating the free energy of aggregates (A) is significantly lower than that for unfolded (U) and native (N) monomers at those particular conditions. The relative thermodynamic stability of A, U, and N states was estimated semi-quantitatively as a function of temperature (T) and [urea] via a combination of calorimetry, urea-assisted unfolding and dissociation, aggregation kinetics, and changes in solvent-exposed surface area, combined with thermodynamic integration and a linear transfer free energy model. The results at first suggest that N is more thermodynamically stable than A at sufficiently low T and [urea], but this may be convoluted with kinetic effects. Interestingly, the kinetic stability of aggregates highlights that the practical measure of stability may be the free energy barrier(s) between A and U, as U serves as a key intermediate between N and A states. (c) 2012 Elsevier B.V. All rights reserved.