α-Synuclein (aSyn) fibrils in Parkinson's disease are generally represented by their ordered cross-β cores, although nearly half of the protein remains disordered in the fibrillar state. The unresolved N- and C-terminal segments form a fuzzy coat that is expected to shape the surface encountered by molecular partners. Here, we reconstructed full-length, brain-derived aSyn Lewy-fold fibrils by extending a patient-derived cryo-EM core spanning residues 31-100, with disordered termini, and sampling the resulting assemblies with the CALVADOS coarse-grained force field. The acidic C-terminal tails established recurrent, transient contacts with solvent-exposed core motifs, especially β5/P2 and β9/P3, generating a dynamic surface in which aggregation-prone ladders are intermittently shielded rather than permanently buried. Simulations with two experimentally validated aSyn-binding peptides, PSMα3 and LL-37, show that peptide recognition follows a two-step process. Cationic peptides are first retained by the anionic fuzzy coat and subsequently engage exposed hydrophobic/electrostatic hotspots on the structured core. PSMα3 variants and LL-37 controls support the importance of positive charge for capture, peptide flexibility for multivalent engagement, and the full-length fibril architecture for persistent binding. These results present a mechanistic model in which selectivity for aggregated aSyn arises from an emergent mesoscale interface combining a polyelectrolyte brush with recurrent core hotspots. Together, these results establish full-length, brain-derived fibril ensembles as a practical framework for understanding ligand recognition at amyloid surfaces.
Carlos Pintado-Grima, O. Bárcenas, G. Tesei et al.· Protein Science· 0 citations
Biomolecular condensates formed by intrinsically disordered proteins require molecular models that accurately describe proteins in both dilute solution and condensed phases. Explicit-solvent coarse-grained models offer an attractive balance between chemical resolution and computational efficiency. Yet, it remains unclear whether improving dilute-state properties is sufficient to obtain an accurate description of condensates. Here, we address this question by introducing minimal modifications to the Martini 3 force field that combine recent advances in bonded interactions with refined protein–water interactions and strengthened glycine self-interactions, while preserving the underlying chemical transferability of the model. The resulting model substantially improves the description of single-chain conformations across a diverse benchmark of disordered proteins. We then investigate phase separation of the well-characterized low-complexity domain of heterogeneous nuclear ribonucleoprotein A1 and its sequence variants. The model reproduces several key physicochemical properties of biomolecular condensates, including chain expansion in the dense phase, sequence-dependent intermolecular contacts, protein diffusion and its relation to single-chain dimensions, and hydration, while revealing quantitative limitations in condensate density, phase equilibria, and ion partitioning. Our results show that improving dilute-state behaviour translates into a better description of condensed-phase properties, including condensate density, but is not sufficient to quantitatively reproduce the equilibrium between the dilute and dense phases.
Fran Bačić Toplek, Luís Borges-Araújo, Kresten Lindorff-Larsen et al.· bioRxiv· 0 citations
A set of coarse-grained two-bead-per-nucleotide models for simulations of double-stranded RNA and DNA in the CALVADOS framework are presented and it is envisioned that the CALVADOS models for double-stranded RNA and DNA will be useful for studying co-condensates of proteins and structured nucleic acids.
Ikki Yasuda, G. Tesei, Eiji Yamamoto et al.· bioRxiv· 0 citations
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