J Chem Theory Comput. 2019 Aug 13;15(8):4708-4720. doi: 10.1021/acs.jctc.9b00397. Epub 2019 Jul 10.
Molecular dynamics simulations using physics-based atomistic force fields have been increasingly used to characterize the heterogeneous structural ensembles of intrinsically disordered proteins (IDPs). To evaluate the accuracy of the latest atomistic explicit-solvent force fields in modeling larger IDPs with nontrivial structural features, we focus on the 61-residue N-terminal transactivation domain (TAD) of tumor suppressor p53, an important protein in cancer biology that has been extensively studied, and abundant experimental data is available for evaluation of simulated ensembles. We performed extensive replica exchange with solute tempering simulations, in excess of 1.0 μs/replica, to generate disordered structural ensembles of p53-TAD using six latest explicit solvent protein force fields. Multiple local and long-range structural properties, including chain dimension, residual secondary structures, and transient long-range contacts, were analyzed and compared against available experimental data. The results show that IDPs such as p53-TAD remain highly challenging for atomistic simulations due to conformational complexity and difficulty in achieving adequate convergence. Structural ensembles of p53-TAD generated using various force fields differ significantly from each other. The a99SB-disp force field demonstrates the best agreement with experimental data at all levels and proves to be suitable for simulating unbound p53-TAD and how its conformational properties may be modulated by phosphorylation and other cellular signals or cancer-associated mutations. Feasibility of such detailed structural characterization is a key step toward establishing the sequence-disordered ensemble-function-disease relationship of p53 and other biologically important IDPs.
使用基于物理原子力场的分子动力学模拟已越来越多地用于描述无规卷曲蛋白质（IDPs）的不均匀结构集合。为了评估最新原子显式溶剂力场在模拟具有复杂结构特征的更大 IDPs 方面的准确性，我们专注于肿瘤抑制因子 p53 的 61 个残基 N 端转录激活结构域（TAD），这是癌症生物学中一个重要的蛋白质，已被广泛研究，并且有大量的实验数据可用于评估模拟集合。我们使用六种最新的显式溶剂蛋白质力场进行了超过 1.0 μs/副本的扩展溶剂温度交换模拟，以生成 p53-TAD 的无序结构集合。分析和比较了多个局部和远程结构特性，包括链尺寸、残基二级结构和瞬态远程接触，以与可用的实验数据进行比较。结果表明，由于构象复杂性和难以实现充分收敛，IDPs 如 p53-TAD 仍然对原子模拟具有很高的挑战性。使用各种力场生成的 p53-TAD 结构集合彼此之间存在显著差异。a99SB-disp 力场在所有级别上与实验数据的一致性最好，并被证明适合模拟未结合的 p53-TAD 以及其构象特性如何通过磷酸化和其他细胞信号或与癌症相关的突变来调节。这种详细结构特征化的可行性是建立 p53 和其他重要生物 IDPs 的序列无序集合-功能-疾病关系的关键步骤。
