The ability to transfer intact proteins and protein complexes into the gas phase by electrospray ionization (ESI) has opened up numerous mass spectrometry (MS)-based avenues for exploring biomolecular structure and function. However, many details regarding the ESI process and the properties of gaseous analyte ions are difficult to decipher when relying solely on experimental data. Molecular dynamics (MD) simulations can provide additional insights into the behavior of ESI droplets and protein ions. This review is geared primarily towards experimentalists who wish to adopt MD simulations as a complementary research tool. We touch on basic points such as force fields, the choice of a proper water model, GPU-acceleration, possible artifacts, as well as shortcomings of current MD models. Following this technical overview, we highlight selected applications. Simulations on aqueous droplets confirm that "native" ESI culminates in protein ion release via the charged residue model. MD-generated charge states and collision cross sections match experimental data. Gaseous protein ions produced by native ESI retain much of their solution structure. Moving beyond classical fixed-charge algorithms, we discuss a simple strategy that captures the mobile nature of H+ within gaseous biomolecules. These mobile proton simulations confirm the high propensity of gaseous proteins to form salt bridges, as well as the occurrence of charge migration during collision-induced unfolding and dissociation. It is hoped that this review will promote the use of MD simulations in ESI-related research. We also hope to encourage the development of improved algorithms for charged droplets and gaseous biomolecular ions.

中文翻译：

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如何对电喷雾液滴和气相蛋白质进行分子动力学模拟：基本指南和选定应用

通过电喷雾电离 (ESI) 将完整蛋白质和蛋白质复合物转移到气相的能力开辟了许多基于质谱 (MS) 的探索生物分子结构和功能的途径。然而，当仅依靠实验数据时，关于 ESI 过程和气态分析物离子特性的许多细节是难以破译的。分子动力学 (MD) 模拟可以提供对 ESI 液滴和蛋白质离子行为的额外见解。本综述主要面向希望采用 MD 模拟作为补充研究工具的实验者。我们涉及基本点，例如力场、适当水模型的选择、GPU 加速、可能的伪影以及当前 MD 模型的缺点。在此技术概述之后，我们突出显示选定的应用程序。对水滴的模拟证实“天然”ESI 最终通过带电残留模型释放蛋白质离子。MD 产生的电荷状态和碰撞截面与实验数据相匹配。由天然 ESI 产生的气态蛋白质离子保留了它们的大部分溶液结构。超越经典的固定电荷算法，我们讨论了一种简单的策略，它可以捕捉气态生物分子中 H+ 的移动性质。这些移动质子模拟证实了气态蛋白质形成盐桥的高度倾向，以及在碰撞诱导的解折叠和解离过程中电荷迁移的发生。希望这篇综述能促进 MD 模拟在 ESI 相关研究中的应用。