Cellmer Troy, Bratko Dusan, Prausnitz John M, Blanch Harvey
Department of Chemical Engineering, University of California, Berkeley, 94720, USA.
J Chem Phys. 2005 May 1;122(17):174908. doi: 10.1063/1.1888545.
Closely related to the "protein folding problem" is the issue of protein misfolding and aggregation. Protein aggregation has been associated with the pathologies of nearly 20 human diseases and presents serious difficulties during the manufacture of pharmaceutical proteins. Computational studies of multiprotein systems have recently emerged as a powerful complement to experimental efforts aimed at understanding the mechanisms of protein aggregation. We describe the thermodynamics of systems containing two lattice-model 64-mers. A parallel tempering algorithm abates problems associated with glassy systems and the weighted histogram analysis method improves statistical quality. The presence of a second chain has a substantial effect on single-chain conformational preferences. The melting temperature is substantially reduced, and the increase in the population of unfolded states is correlated with an increase in interactions between chains. The transition from two native chains to a non-native aggregate is entropically favorable. Non-native aggregates receive approximately 25% of their stabilizing energy from intraprotein contacts not found in the lowest-energy structure. Contact maps show that for non-native dimers, nearly 50% of the most probable interprotein contacts involve pairs of residues that form native contacts, suggesting that a domain-swapping mechanism is involved in self-association.
与“蛋白质折叠问题”密切相关的是蛋白质错误折叠和聚集的问题。蛋白质聚集与近20种人类疾病的病理状况相关，并且在药用蛋白质的生产过程中带来了严重困难。多蛋白质系统的计算研究最近已成为旨在理解蛋白质聚集机制的实验工作的有力补充。我们描述了包含两个晶格模型64聚体的系统的热力学。并行回火算法减轻了与玻璃态系统相关的问题，加权直方图分析方法提高了统计质量。第二条链的存在对单链构象偏好有重大影响。解链温度大幅降低，未折叠状态群体的增加与链间相互作用的增加相关。从两条天然链到非天然聚集体的转变在熵上是有利的。非天然聚集体约25%的稳定能量来自最低能量结构中未发现的蛋白质内接触。接触图表明，对于非天然二聚体，近50%最可能的蛋白质间接触涉及形成天然接触的残基对，这表明结构域交换机制参与了自组装。
