25 research outputs found
Molecular Interpretation of ACTH-β-Endorphin Coaggregation: Relevance to Secretory Granule Biogenesis
Peptide/protein hormones could be stored as non-toxic amyloid-like structures in pituitary secretory granules. ACTH and β-endorphin are two of the important peptide hormones that get co-stored in the pituitary secretory granules. Here, we study molecular interactions between ACTH and β-endorphin and their colocalization in the form of amyloid aggregates. Although ACTH is known to be a part of ACTH-β-endorphin aggregate, ACTH alone cannot aggregate into amyloid under various plausible conditions. Using all atom molecular dynamics simulation we investigate the early molecular interaction events in the ACTH-β-endorphin system, β-endorphin-only system and ACTH-only system. We find that β-endorphin and ACTH formed an interacting unit, whereas negligible interactions were observed between ACTH molecules in ACTH-only system. Our data suggest that ACTH is not only involved in interaction with β-endorphin but also enhances the stability of mixed oligomers of the entire system
Role of non-specific interactions in the phase-separation and maturation of macromolecules.
Phase separation of biomolecules could be mediated by both specific and non-specific interactions. How the interplay between non-specific and specific interactions along with polymer entropy influences phase separation is an open question. We address this question by simulating self-associating molecules as polymer chains with a short core stretch that forms the specifically interacting functional interface and longer non-core regions that participate in non-specific/promiscuous interactions. Our results show that the interplay of specific (strength, ϵsp) and non-specific interactions (strength, ϵns) could result in phase separation of polymers and its transition to solid-like aggregates (mature state). In the absence of ϵns, the polymer chains do not dwell long enough in the vicinity of each other to undergo phase separation and transition into a mature state. On the other hand, in the limit of strong ϵns, the assemblies cannot transition into the mature state and form a non-specific assembly, suggesting an optimal range of interactions favoring mature multimers. In the scenario where only a fraction (Nfrac) of the non-core regions participate in attractive interactions, we find that slight modifications to either ϵns or Nfrac can result in dramatically altered self-assembled states. Using a combination of heterogeneous and homogeneous mix of polymers, we establish how this interplay between interaction energies dictates the propensity of biomolecules to find the correct binding partner at dilute concentrations in crowded environments
Defining a Physical Basis for Diversity in Protein Self-Assemblies Using a Minimal Model
Self-assembly of proteins into ordered,
fibrillar structures is
a commonly observed theme in biology. It has been observed that diverse
set of proteins (e.g., alpha-synuclein, insulin, TATA-box binding
protein, Sup35, p53), independent of their sequence, native structure,
or function could self-assemble into highly ordered structures known
as amyloids. What are the crucial features underlying amyloidogenesis
that make it so generic? Using coarse-grained simulations of peptide
self-assembly, we argue that variation in two physical parametersbending
stiffness of the polypeptide and strength of intermolecular interactionscan
give rise to many of the structural features typically associated
with amyloid self-assembly. We show that the interplay between these
two factors gives rise to a rich phase diagram displaying high diversity
in aggregated states. For certain parameters, we find a bimodal distribution
for the order parameter implying the coexistence of ordered and disordered
aggregates. Our findings may explain the experimentally observed variability
including the “off-pathway” aggregated structures. Further,
we demonstrate that sequence-dependence and protein-specific signatures
could be mapped to our coarse-grained framework to study self-assembly
behavior of realistic systems such as the STVIIE peptide and Aβ42.
The work also provides certain guiding principles that could be used
to design novel peptides with desired self-assembly properties, by
tuning a few physical parameters
Defining a Physical Basis for Diversity in Protein Self-Assemblies Using a Minimal Model
Self-assembly of proteins into ordered,
fibrillar structures is
a commonly observed theme in biology. It has been observed that diverse
set of proteins (e.g., alpha-synuclein, insulin, TATA-box binding
protein, Sup35, p53), independent of their sequence, native structure,
or function could self-assemble into highly ordered structures known
as amyloids. What are the crucial features underlying amyloidogenesis
that make it so generic? Using coarse-grained simulations of peptide
self-assembly, we argue that variation in two physical parametersbending
stiffness of the polypeptide and strength of intermolecular interactionscan
give rise to many of the structural features typically associated
with amyloid self-assembly. We show that the interplay between these
two factors gives rise to a rich phase diagram displaying high diversity
in aggregated states. For certain parameters, we find a bimodal distribution
for the order parameter implying the coexistence of ordered and disordered
aggregates. Our findings may explain the experimentally observed variability
including the “off-pathway” aggregated structures. Further,
we demonstrate that sequence-dependence and protein-specific signatures
could be mapped to our coarse-grained framework to study self-assembly
behavior of realistic systems such as the STVIIE peptide and Aβ42.
The work also provides certain guiding principles that could be used
to design novel peptides with desired self-assembly properties, by
tuning a few physical parameters