Testing the Robustness of Solution Force Fields for MD Simulations on Gaseous Protein Ions.

It is believed that electrosprayed proteins and protein complexes can retain solution-like conformations in the gas phase. However, the lack of high-resolution structure determination methods for gaseous protein ions implies that their properties remain poorly understood. Many practitioners tackle this difficulty by complementing mass spectrometry-based experiments with molecular dynamics (MD) simulations. It is a potential problem that the standard MD force fields used for this purpose (such as OPLS-AA/L and CHARMM) were optimized for solution conditions. The question whether these force fields produce meaningful gas-phase data has received surprisingly little attention. Standard force fields are overpolarized to account for an aqueous environment, i.e., atomic charges and intramolecular dipole moments are ∼20% larger than predicted by gas-phase ab initio methods. Here, we examined the implications of this overpolarization by conducting a series of MD simulations on electrosprayed proteins. Force fields were modified via a charge scaling factor (CSF), while ensuring that the net protein charge remained unchanged. CSF = 0.8 should roughly eliminate water-associated overpolarization. Gas-phase CHARMM simulations on myoglobin with CSF = 0.8 and with unmodified parameters (CSF = 1) yielded similar results, preserving a compact structure that was consistent with ion mobility experiments. Major structural changes caused by weakened charge-dipole and dipole-dipole contacts occurred only when lowering CSF to physically unreasonable values (0.5 and 0.1). Similar results were obtained in mobile-proton OPLS-AA/L simulations on the collision-induced dissociation of transthyretin. Our data support the view that gas-phase MD simulations with standard (solution) force fields are suitable for modeling gaseous protein ions in a semiquantitative manner. Although this is welcome news for the mass spectrometry community, it is hoped that dedicated gas-phase MD force fields will become available in the near future.