Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, 52425 Jülich, Germany; Institute of Theoretical and Computational Chemistry, Heinrich Heine University Düsseldorf, Universitätstrasse 1, 40225 Düsseldorf, Germany.
Curr Opin Struct Biol. 2021 Apr;67:145-152. doi: 10.1016/j.sbi.2020.10.019. Epub 2020 Dec 3.
In amyloid aggregation diseases soluble proteins coalesce into a wide array of undesirable structures, ranging through oligomers and prefibrillar assemblies to highly ordered amyloid fibrils and plaques. Explicit-solvent all-atom molecular dynamics (MD) simulations of amyloid aggregation have been performed for almost 20 years, revealing valuable information about this phenomenon. However, these simulations are challenged by three main problems. Firstly, current force fields modeling amyloid aggregation are insufficiently accurate. Secondly, the protein concentrations in MD simulations are usually orders of magnitude higher than those used in vitro or found in vivo, which has direct consequences on the aggregates that form. Finally, the third problem is the well-known time-scale limit of MD simulations. In this review I highlight recent approaches to overcome these three limitations.
在淀粉样蛋白聚集疾病中，可溶性蛋白凝聚成各种不理想的结构，范围从低聚物和前纤维组装体到高度有序的淀粉样纤维和斑块。对淀粉样蛋白聚集的明溶剂全原子分子动力学 (MD) 模拟已经进行了近 20 年，揭示了有关这一现象的有价值的信息。然而，这些模拟受到三个主要问题的挑战。首先，目前用于模拟淀粉样蛋白聚集的力场不够准确。其次，MD 模拟中的蛋白质浓度通常比体外或体内使用的浓度高出几个数量级，这对形成的聚集体有直接影响。最后，第三个问题是 MD 模拟众所周知的时间尺度限制。在这篇综述中，我强调了最近克服这三个限制的方法。
