title: Intrinsic disorder modulates protein self-assembly and aggregation.
abstract: Protein molecules have evolved to adopt distinctive and well-defined functional and soluble states under physiological conditions. In some circumstances, however, proteins can self-assemble into fibrillar aggregates designated as amyloid fibrils. In vivo these processes are normally associated with severe pathological conditions but can sometimes have functional relevance. One such example is the hydrophobins, whose aggregation at air-water interfaces serves to create robust protein coats that help fungal spores to resist wetting and thus facilitate their dispersal in the air. We have performed multiscale simulations to address the molecular determinants governing the formation of functional amyloids by the class I fungal hydrophobin EAS. Extensive samplings of full-atom replica-exchange molecular dynamics and coarse-grained simulations have allowed us to identify factors that distinguish aggregation-prone from highly soluble states of EAS. As a result of unfavourable entropic terms, highly dynamical regions are shown to exert a crucial influence on the propensity of the protein to aggregate under different conditions. More generally, our findings suggest a key role that specific flexible structural elements can play to ensure the existence of soluble and functional states of proteins under physiological conditions.
authors.affiliation: Division of Molecular Biosciences, Imperial College London, South Kensington SW7 2AZ, United Kingdom.
authors.forename: Alfonso
authors.initials: A
authors.lastname: De Simone
authors.forename: Craig
authors.initials: C
authors.lastname: Kitchen
authors.forename: Ann H
authors.initials: AH
authors.lastname: Kwan
authors.forename: Margaret
authors.initials: M
authors.lastname: Sunde
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.forename: Daan
authors.initials: D
authors.lastname: Frenkel
mesh_terms: D000388:Air; D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry; D055592:Biophysical Phenomena; D003198:Computer Simulation; D019277:Entropy; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D012995:Solubility; D014867:Water
chemical_list: D000682:Amyloid; D005656:Fungal Proteins; D014867:Water