Recalibration of protein interactions in Martini 3

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Multidomain proteins with flexible linkers and disordered regions play important roles in many cellular processes, but characterizing their conformational ensembles is difficult. In simulations, the situation is complicated further in multi-component systems—such as in the presence of a membrane—since the conformational ensemble depends on subtle balances between the interactions between and within protein, membrane, and water. We have previously shown that, for intrinsically disordered proteins (IDPs) and a small set of multidomain proteins, the widely used coarse grained force field, Martini 3, produces too compact ensembles in solution, and that increasing the strength of protein-water interactions in Martini 3 (by 10%) improves the agreement between simulations and small-angle X-ray scattering (SAXS) for these proteins. Here, we examine whether, as an alternative approach, decreasing the strength of interactions between protein beads can provide equivalent or further improved agreement with the experimental data, and explore the effects of these choices on the interactions with lipid bilayers. We have expanded the set of multidomain proteins to include a wider variety of sizes and domain architectures. Consistent with our previous results, we find that Martini 3 underestimates the global dimensions of this set of multidomain proteins, and that increasing the strength of protein-water interactions (by 10%) or decreasing the strength of non-bonded interactions between protein beads (by 12%) substantially improves the agreement with experimental SAXS data. We show that the ‘symmetry’ between rescaling protein-water and protein-protein interactions breaks down when studying interactions with membranes, and that rescaling protein-protein interactions better preserves the binding specificity of peripheral membrane proteins, multidomain proteins, and IDPs with lipid membranes. We conclude that decreasing the strength of protein-protein interactions improves the accuracy of Martini 3 for IDPs and multidomain proteins, both in solution and in the presence of a lipid membrane, providing a favorable alternative to rescaling protein-water interactions.

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