High-Performance\nMolecular Dynamics Simulations for\nNative Mass Spectrometry of Large Protein Complexes with the Fast\nMultipole Method

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