Neurodegenerative diseases are closely linked to aberrant protein aggregation arising from failures in cellular proteostasis, yet the physical determinants governing transitions between soluble states

The gap

Consensus across the literature

Supporting evidence — 3 representative gaps

• From the classical colloidal theory to biomolecular condensation: implications in health and disease (2026) · doi

  Spontaneous biomolecules segregation into concentrated liquid- like droplets constitutes a new paradigm in protein biophysics, with deep implications for our understanding of normal and abnormal cellular biochemistry. Condensation implies a higher level of organization in the protein-energy landscape. The folding and function of single protein molecules, as described by the still- valid Anfinsen’s dogma, are now seen as part of a collective of molecules orchestrated to optimize physical and biological properties, allowing proteins to reach concentrations beyond their solubility limits (see Figure 1). The assembly-disassembly tightly modulated by dynamics of biocondensates environmental factors like pH, temperature, cofactors (metal ions), ionic strength, PTMs, crowding and others. This provides a complex mechanism for regulating cellular processes adding a new dimension to the relationship between protein sequence, structure and cellular function. are Phase separation frequently represents the initial step in the protein aggregation pathway within the folding energy landscape and commonly results in the formation of amyloid fibrils. Importantly, the emergence of catalytic activities within these supramolecular scaffolds reframe amyloidogenic transitions as shifts toward non-canonical enzymatic states rather than only pathological misfolding. Consequently, the therapeutic frontier should evolve from inhibiting aggregation to embracing the concept of interfacial pharmacology (Kochman et al., 2025; Fleming and Schuijers, 2026). By targeting the rheological properties and thermodynamic stability of biocondensates, it becomes possible to move beyond aggregate dissolution and toward protein energy landscape. the deliberate reprogramming the of acquisition, Investigation. ME: Conceptualization, Supervision, Writing – review and editing, Investigation. DV: Investigation, Project Conceptualization, Funding acquisition, administration, draft, – Supervision, Writing Writing – review and editing.

  Keywords: protein cellular energy landscape investigation writing like folding function molecules properties beyond biocondensates aggregation within
• Tightly Knotted Enzymes Inhibit Protein-Protein Aggregation (2026) · doi

  Neurodegenerative diseases are closely linked to aberrant protein aggregation arising from failures in cellular proteostasis, yet the physical determinants governing transitions between soluble states, liquid liquid phase separation (LLPS), and aggregation remain incompletely understood.

  Keywords: aggregation liquid neurodegenerative diseases closely linked aberrant protein arising failures cellular proteostasis physical determinants governing
• Fusion protein condensate formation via coiled‐coil domains (2026) · doi

  Abstract While recent research shows that biomolecular condensates play important roles in normal cellular processes and diseases, the driving forces in condensate formation are not well understood, especially regarding the role of structured self‐associative protein domains.

  Keywords: abstract recent shows biomolecular condensates play important roles normal cellular processes diseases driving forces condensate