In-cell protein–protein association, which is crucial in enzyme catalysis and polymerization, occurs in an environment that is highly heterogeneous and crowded. The crowder molecules exclude the reactant molecules from occupying certain regions of the cell, resulting in changes in the reaction thermodynamics and kinetics. Recent studies, both experiment and simulations, revealed that the nature of the interaction between crowder and protein species, in particular the soft interactions, plays an important role in crowder induced effects on protein association. To this end, from a simulation perspective, it is important to decipher the level of structural resolution in a protein-crowder model that can faithfully capture the influence of crowding on protein association. Here, we investigate the dimerization of model system GB1 in the presence of lysozyme crowders at two structural resolutions. The lower resolution model assumes both protein and crowder species as spherical beads, similar to the analytical scaled particle theory model, whereas the higher resolution model retains residue specific structural details for protein and crowder species. From the higher resolution model, it is found that GB1 dimer formation is destabilized in the presence of lysozyme crowders, and the destabilization is more for the side-by-side dimer compared to the domain-swapped dimer, in qualitative agreement with experimental findings. However, the low resolution CG model predicts stabilization of the dimers in the presence of the lysozyme crowder, similar to the SPT model. Our results indicate a nontrivial role of the choice of model resolution in computer simulation studies investigating crowder induced effects.

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Amyloid-beta (Ab) aggregation mediated neuronal membrane deformation, although poorly understood, is implicated in Alzheimer's Disease (AD). Particularly, whether Ab aggregation can induce neuronal demyelination remains unknown. Here we show that Aβ-40 binds and induces extensive tubulation in the myelin membrane in vitro. The binding of Aβ-40 depends predominantly on the lipid packing defect densities and electrostatic interactions and results in rigidification of the myelin membrane in the early time scales. Furthermore, elongation of Aβ-40 into higher oligomeric and fibrillar species leads to eventual fluidization of the myelin membrane followed by extensive membrane tubulation observed in the late phase. Taken together, our results capture mechanistic insights into snapshots of temporal dynamics of Aβ-40- myelin membrane interaction and demonstrate how short timescale, local phenomena of binding, and fibril mediated load generation manifests into long timescale, global phenomena of myelin tubulation and demonstrates the ability of Aβ-40 to demyelinate.