A toy model for predicting the rate of amyloid formation from unfolded protein
A toy model for predicting the rate of amyloid formation from unfolded protein
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DOI：
10.1016/j.jmb.2005.05.013
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发表时间：
2005-08-05
影响因子：
5.6
通讯作者：
Dobson, CM
中科院分区：
文献类型：
--
作者：
Hall, D;Hirota, N;Dobson, CM
我们开发了一个玩具模型，用于预测未折叠多肽的淀粉样蛋白形成速率。该模型假设不可逆的淀粉样蛋白的生长，采用碰撞遇到计划，并使用高斯链近似来描述的多肽序列。该模型的一个主要特征是它依赖于一些关键序列残基，其正确的位置，几何排列和方向，相对于它们的相互作用的合作伙伴定义的成功，或否则，淀粉样蛋白形成反应。虽然在分子水平上不现实，但该模型捕捉了系统的一些基本特征，因此从启发式的角度来看是有用的。对于从非结构化状态的淀粉样蛋白形成的情况下，该模型表明，原纤维形成的速率的主要决定因素是分离促进淀粉样蛋白形成的关键氨基酸的序列的长度和序列内的关键残基的位置放置。我们的研究结果还表明，关键相互作用的氨基酸残基之间的序列距离可能在定义纤维的最大宽度中发挥作用，并且向淀粉样蛋白生成肽添加长的无结构多肽链的非相互作用片段可能起到抑制纤维形成的作用。我们讨论了这些发现与参考的多肽链内的关键序列残基的位置，具有较低的淀粉样蛋白形成倾向的多肽的设计和聚集抑制剂作为潜在的治疗蛋白沉积障碍的发展。爱思唯尔有限公司出版
We develop a toy model for predicting the rate of amyloid formation from an unfolded polypeptide. The model assumes irreversible amyloid growth, employs a collision encounter scheme and uses a Gaussian chain approximation to describe the polypeptide sequence. A principal feature of the model is its dependence on a number of key sequence residues whose correct placement, geometric arrangement and orientation in relation to their interacting partners define the success, or otherwise, of the amyloid formation reaction. Although not realistic at the molecular level, the model captures some essential features of the system and is therefore useful from a heuristic standpoint. For the case of amyloid formation from an unstructured state, the model suggests that the major determinants of the rate of fibril formation are the length of the sequence separating the critical amino acids promoting amyloid formation and the positional placement of the critical residues within the sequence. Our findings suggest also that the sequence distance between the key interacting amino acid residues may play a role in defining the maximum width of a fibril and that the addition of non-interacting segments of long structure-less polypeptide chain to an amyloidogenic peptide may act to inhibit fibril formation. We discuss these findings with reference to the placement of critical sequence residues within the polypeptide chain, the design of polypeptides with lower amyloid formation propensities and the development of aggregation inhibitors as potential therapeutics for protein depositional disorders. Published by Elsevier Ltd.