A Systematic Framework for Molecular Dynamics Simulations of Protein Post-Translational Modifications

By directly affecting structure, dynamics and interaction networks of their targets, post-translational modifications (PTMs) of proteins play a key role in different cellular processes ranging from enzymatic activation to regulation of signal transduction to cell-cycle control. Despite the great importance of understanding how PTMs affect proteins at the atomistic level, a systematic framework for treating post-translationally modified amino acids by molecular dynamics (MD) simulations, a premier high-resolution computational biology tool, has never been developed. Here, we report and validate force field parameters (GROMOS 45a3 and 54a7) required to run and analyze MD simulations of more than 250 different types of enzymatic and non-enzymatic PTMs. The newly developed GROMOS 54a7 parameters in particular exhibit near chemical accuracy in matching experimentally measured hydration free energies (RMSE = 4.2 kJ/mol over the validation set). Using this tool, we quantitatively show that the majority of PTMs greatly alter the hydrophobicity and other physico-chemical properties of target amino acids, with the extent of change in many cases being comparable to the complete range spanned by native amino acids.

蛋白质翻译后修饰（post-translational modifications, PTMs）可直接调控靶标蛋白的结构、动力学特性与相互作用网络，在从酶激活、信号转导调控到细胞周期控制等诸多细胞过程中发挥关键作用。尽管解析翻译后修饰如何在原子层面影响蛋白质的机制具有重要意义，但目前尚未建立起一套可通过分子动力学（molecular dynamics, MD）模拟——这一顶尖高分辨率计算生物学工具——来处理翻译后修饰氨基酸的系统性框架。本研究构建并验证了可用于运行与分析250余种酶促及非酶促翻译后修饰的分子动力学模拟所需的力场参数（GROMOS 45a3与54a7）。其中新开发的GROMOS 54a7参数在匹配实验测得的水合自由能时，几乎达到化学精度，验证集上的均方根误差（root mean square error, RMSE）为4.2 kJ/mol。借助这一工具，我们定量证实绝大多数翻译后修饰会显著改变靶标氨基酸的疏水性及其他理化性质，其改变幅度在诸多情况下可与天然氨基酸的性质变化全范围相媲美。