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首页> 外文期刊>Journal of Molecular Biology >Establishment of Constraints on Amyloid Formation Imposed by Steric Exclusion of Globular Domains
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Establishment of Constraints on Amyloid Formation Imposed by Steric Exclusion of Globular Domains

机译：间隙域抑制淀粉样蛋白形成的约束

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摘要

In many disease-related and functional amyloids, the amyloid-forming regions of proteins are flanked by globular domains. When located in close vicinity of the amyloid regions along the chain, the globular domains can prevent the formation of amyloids because of the steric repulsion. Experimental tests of this effect are few in number and non-systematic, and their interpretation is hampered by polymorphism of amyloid structures. In this situation, modeling approaches that use such a clear-cut criterion as the steric tension can give us highly trustworthy results. In this work, we evaluated this steric effect by using molecular modeling and dynamics. As an example, we tested hybrid proteins containing an amyloid-forming fragment of A beta peptide (17-42) linked to one or two globular domains of GFP. Searching for the shortest possible linker, we constructed models with pseudo-helical arrangements of the densely packed GFPs around the A beta amyloid core. The molecular modeling showed that linkers of 7 and more residues allow fibrillogenesis of the A beta-peptide flanked by GFP on one side and 18 and more residues when A beta-peptide is flanked by GFPs on both sides. Furthermore, we were able to establish a more general relationship between the size of the globular domains and the length of the linkers by using analytical expressions and rigid body simulations. Our results will find use in planning and interpretation of experiments, improvement of the prediction of amyloidogenic regions in proteins, and design of new functional amyloids carrying globular domains. (C) 2018 Elsevier Ltd. All rights reserved.
机译：在许多疾病相关和功能性淀粉样蛋白中，蛋白质的淀粉样蛋白形成区域侧翼为球状结构域。当位于沿着链条的淀粉样蛋白区附近时，球状结构域可以防止由于空间排斥而形成淀粉样蛋白。这些效果的实验测试数量很少，非系统性少，并且它们的解释被淀粉样蛋白结构的多态性阻碍了。在这种情况下，使用这种清除标准的建模方法作为空间张力可以给我们高度值得信赖的结果。在这项工作中，我们通过使用分子建模和动态来评估该空间效果。作为一个例子，我们测试了含有与GFP的一个或两个球状球域连接的β肽（17-42）的淀粉样蛋白形成片段的杂化蛋白。搜索最短的链接器，我们构造了诸如β淀粉样芯周围密集包装的GFP的伪螺旋布置的型号。分子建模表明，7和更多残基的接头允许在一侧和18侧翼的GFP上侧翼的β-肽的原纤维生成，并且当β-肽在两侧的GFP侧翼侧翼时，β-肽。此外，我们能够通过使用分析表达和刚体模拟来建立球形域的大小和接头长度之间的更一般的关系。我们的结果将在规划和解释实验中，改进蛋白质中淀粉样蛋白区域的预测，以及携带球状结构球的新功能淀粉样蛋白的设计。 （c）2018年elestvier有限公司保留所有权利。

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