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Charge hopping in coarse-grained simulations of gas-phase protein complexes Fegan, Sarah Katherine

Abstract

With the invention of gentle ionization methods such as electrospray ionization, mass spectrometry has been used as a tool for studying large protein complexes. Simulations of these gas-phase protein complexes will allow for better understanding of the dissociation mechanism and lead to methods for controlling the dissociation. Controlling the dissociation will help obtain structural information from the mass spectrometry experiments.In this work, the suitability of the MARTINI coarse-grained force field for gas-phase simulations is studied and a charge hopping algorithm is developed. Using a coarse-grained force field makes the simulations faster so that longer simulation times can be accessed. This is important because protein motions can take place on time scales of nanoseconds to milliseconds and these long times are not practical with all-atom simulations. Most molecular dynamics simulations use fixed charges, but including charge motion allows for better simulation of mobile protons.Two protein complexes are studied here, one dimer and one tetramer. Hopping rates, energies, radii of gyration, and distances within the complexes are calculated. Simulations with the cytochrome c$^{\prime}$ dimer (no charge hopping) are compared to published all-atom results. The MARTINI force field is found to be good for qualitative results, but slightly more attractive than the OPLS all-atom (for the isolated protein complex). The transthyretin tetramer is used to study the hopping algorithm. Modifications of the protein (blocking N-termini from accepting charges and adding basic sites with a tether) are also explored. The dissociation behavior of the protein complexes is controlled by the Coulomb repulsion model. Protein modifications near the N-termini show potential for controlling the dissociation.

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