Structural and Thermodynamic Characteristics That Seed Aggregation of Amyloid-尾 Protein in Water
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- 作者：Song-Ho Chong ; Mirae Park ; Sihyun Ham
- 刊名：Journal of Chemical Theory and Computation
- 出版年：2012
- 出版时间：February 14, 2012
- 年：2012
- 卷：8
- 期：2
- 页码：724-734
- 全文大小：549K
- 年卷期：v.8,no.2(February 14, 2012)
- ISSN：1549-9626
文摘
Amyloid-尾 (A尾) proteins undergo conformational transitions leading to aggregation-prone structures, which can initiate self-assembly to form soluble oligomers and eventually insoluble amyloid fibrils when transferred from the transmembrane phase to the physiological aqueous phase. Yet, how A尾 proteins acquire an aggregation-prone nature during the conformational transitions in water remains elusive. Here, we investigate key structural and thermodynamic features of a 42-residue A尾 (A尾42) protein that seed aggregation based on the fully atomistic, explicit-water molecular dynamics simulations as well as on the integral-equation theory of liquids for solvation thermodynamic analysis. We performed a structure-based analysis on the solvation free energy, a major determinant of the protein hydrophobicity/solubility that influences the aggregation propensity of A尾42 protein in water. In addition, the Gibbs free energy and its constituents including protein internal energy, protein configurational entropy, solvation enthalpy, and solvation entropy were computed to elucidate thermodynamic driving forces for the conformational transitions of A尾42 protein in water. On the basis of the atomic-decomposition analysis of these thermodynamic functions, we demonstrate how N-terminal (residues 1鈥?1) and C-terminal (39鈥?2) regions as well as the central region (16鈥?8) contribute significantly to decreasing the solubility of A尾42 protein upon its conformational transitions in water. These results are consistent with the recent experimental and computational implications and further provide the molecular origin for why the C terminus may serve as an 鈥渋nternal seed鈥?for aggregation and the N-terminal segment may act as a 鈥渃atalyst鈥?in inducing the A尾42 self-assembly. This work takes a step forward toward the identification of structural and thermodynamic features of the A尾42 monomer that seed the aggregation process in water.