Proton Transfers to DNA in Native Electrospray Ionization Mass Spectrometry: A Quantum Mechanics/Molecular Mechanics Study

Native electrospray ionization-ion mobility mass spectrometry (N-ESI/IM-MS) is a powerful approach for low-resolution structural studies of DNAs in the free state and in complex with ligands. Solvent vaporization is coupled with proton transfers from ammonium ions to the DNA, resulting in a reduction of the DNA charge. Here we provide insight into these processes by classical molecular dynamics and quantum mechanics/molecular mechanics free energy calculations on the d(GpCpGpApApGpC) heptamer, for which a wealth of experiments is available. Our multiscale simulations, consistent with experimental data, reveal a highly complex scenario. The proton either sits on one of the molecules or is fully delocalized on both, depending on the level of hydration of the analytes and the size of the droplets formed during the electrospray experiments. This work complements our previous study of the intramolecular proton transfer on the same heptamer occurring after the processes studied here, and together, they provide a first molecular view of proton transfer in N-ESI/IM-MS.

原生电喷雾电离-离子迁移质谱法（Native electrospray ionization-ion mobility mass spectrometry，N-ESI/IM-MS）是一种用于游离态DNA及配体结合态DNA低分辨率结构研究的有力工具。该过程中，溶剂汽化与铵离子向DNA的质子转移耦合发生，进而降低DNA所带电荷。本研究针对d(GpCpGpApApGpC)七聚体，通过经典分子动力学（classical molecular dynamics）及量子力学/分子力学（quantum mechanics/molecular mechanics）自由能计算，对上述过程开展深入解析——该七聚体已有丰富的实验数据支撑。我们的多尺度模拟与实验数据吻合良好，揭示出极为复杂的过程图景：质子要么结合于其中一个分子，要么完全离域于两个分子之间，这一分布状态取决于分析物的水合程度及电喷雾实验中形成的液滴尺寸。本研究对我们此前针对该七聚体、在本研究探讨的过程之后发生的分子内质子转移的相关研究进行了补充，二者共同为N-ESI/IM-MS中的质子转移提供了首个分子层面的解析视角。