High-Performance Molecular Dynamics Simulations for Native Mass Spectrometry of Large Protein Complexes with the Fast Multipole Method.

Native mass spectrometry (MS) is widely employed to study the structures and assemblies of proteins ranging from small monomers to megadalton complexes. Molecular dynamics (MD) simulation is a useful complement as it provides the spatial detail that native MS cannot offer. However, MD simulations performed in the gas phase have suffered from rapidly increasing computational costs with the system size. The primary bottleneck is the calculation of electrostatic forces, which are effective over long distances and must be explicitly computed for each atom pair, precluding efficient use of methods traditionally used to accelerate condensed-phase simulations. As a result, MD simulations have been unable to match the capacity of MS in probing large multimeric protein complexes. Here, we apply the fast multipole method (FMM) for computing the electrostatic forces, recently implemented by Kohnke et al. ( J. Chem. Theory Comput., 2020 , 16 , 6938-6949), showing that it significantly enhances the performance of gas-phase simulations of large proteins. We assess how to achieve adequate accuracy and optimal performance with FMM, finding that it expands the accessible size range and time scales dramatically. Additionally, we simulate a 460 kDa ferritin complex over microsecond time scales, alongside complementary ion mobility (IM)-MS experiments, uncovering conformational changes that are not apparent from the IM-MS data alone.