Molecular dynamics simulations of intrinsically disordered proteins p53TAD and Pup

Intrinsically disordered proteins (IDPs) are highly dynamic systems that play an important role in cell signaling processes and their misfunction often causes human disease. Proper understanding of IDP function not only requires the realistic characterization of their three-dimensional conformational ensembles at atomic-level resolution but also of the time scales of interconversion between their conformational substates. Large sets of experimental data are often used in combination with molecular modeling to restrain or bias models to improve agreement with experiment. It is shown here for the N-terminal transactivation domain of p53 (p53TAD) and Pup how the latest advancements in molecular dynamics (MD) simulations methodology produces native conformational ensembles by combining replica exchange with series of microsecond MD simulations. They closely reproduce experimental data at the global conformational ensemble level, in terms of the distribution properties of the radius of gyrat..., ,

内在无序蛋白（Intrinsically disordered proteins, IDPs）是一类高度动态的生物体系，在细胞信号转导过程中发挥关键作用，其功能异常常可引发人类疾病。要正确认识IDP的功能，不仅需要以原子级分辨率对其三维构象系综进行精准表征，还需解析其构象亚态间的相互转换时间尺度。研究中常将大规模实验数据与分子建模相结合，通过约束或偏置模型来提升模型与实验结果的契合度。本研究以p53的N端反式激活结构域（p53TAD）以及Pup为研究对象，展示了分子动力学（Molecular Dynamics, MD）模拟方法的最新进展如何通过将副本交换与一系列微秒级分子动力学模拟相结合，生成符合天然状态的构象系综。该构象系综在全局构象层面可精准复现实验数据，具体体现为回转半径的分布特征……