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.

Automated summary

The authors used classical molecular dynamics and quantum mechanics/molecular mechanics methods to investigate proton transfer processes in N-ESI/IM-MS, and validated the simulation results with experimental data. The study revealed that the distribution of protons depends on the hydration level of the analytes and the size of droplets formed during electrospray experiments.