483 research outputs found
The structure of amyloid versus the structure of globular proteins
The issue of changing the structure of globular proteins into an amyloid form is in the focus
of researchers' attention. Numerous experimental studies are carried out, and mathematical models
to define the essence of amyloid transformation are sought. The present work focuses on the issue of
the hydrophobic core structure in amyloids. The form of ordering the hydrophobic core in globular
proteins is described by a 3D Gaussian distribution analog to the distribution of hydrophobicity in a
spherical micelle. Amyloid fibril is a ribbon-like micelle made up of numerous individual chains,
each representing a flat structure. The distribution of hydrophobicity within a single chain included
in the fibril describes the 2D Gaussian distribution. Such a description expresses the location of polar
residues on a circle with a center with a high level of hydrophobicity. The presence of this type of
order in the amyloid forms available in Preotin Data Bank (PDB) (both in proto- and superfibrils) is
demonstrated in the present work. In this system, it can be assumed that the amyloid transformation
is a chain transition from 3D Gauss ordering to 2D Gauss ordering. This means changing the globular
structure to a ribbon-like structure. This observation can provide a simple mathematical model for
simulating the amyloid transformation of proteins
The amyloid as a ribbon-like micelle in contrast to spherical micelles represented by globular proteins
Selected amyloid structures available in the Protein Data Bank have been subjected to
a comparative analysis. Classification is based on the distribution of hydrophobicity in amyloids
that differ with respect to sequence, chain length, the distribution of beta folds, protofibril structure,
and the arrangement of protofibrils in each superfibril. The study set includes the following amyloids:
(1-42), which is listed as (15-40) and carries the D23N mutation, and (11-42) and
(1-40), both of which carry the mutation, tau amyloid, and -synuclein. Based on the fuzzy oil
drop model (FOD), we determined that, despite their conformational diversity, all presented amyloids
adopt a similar structural pattern that can be described as a ribbon-like micelle. The same model,
when applied to globular proteins, results in structures referred to as "globular micelles," emerging
as a result of interactions between the proteins' constituent residues and the aqueous solvent. Due to
their composition, amyloids are unable to attain entropically favorable globular forms and instead
attempt to limit contact between hydrophobic residues and water by producing elongated structures.
Such structures typically contain quasi hydrophobic cores that stretch along the fibril’s long axis.
Similar properties are commonly found in ribbon-like micelles, with alternating bands of high and
low hydrophobicity emerging as the fibrils increase in length. Thus, while globular proteins are
generally consistent with a 3D Gaussian distribution of hydrophobicity, the distribution instead
conforms to a 2D Gaussian distribution in amyloid fibrils
Internal force field in selected proteins
The fuzzy oil drop model suggests that the tertiary conformation of a protein – particularly a globular one - can
be likened to a spherical micelle. During the folding process, hydrophilic residues are exposed on the surface,
while hydrophobic residues are retained inside the protein. The resulting hydrophobicity distribution can be
mathematically modeled as a 3D Gaussian. The fuzzy oil
drop model is strikingly effective in explaining the properties of type II antifreeze proteins and fast-folding proteins, as well as a vast majority of autonomous protein
domains. This work aims to determine whether similar
mechanisms apply to other types of nonbonding interactions. Our analysis indicates that electrostatic and van
der Waals forces do not conform to the Gaussian pattern. The study involves a reference protein (titin) which
shows a high agreement between the observed distribution of hydrophobicity and the theoretical (Gaussian)
distribution, a selection of amyloid structures derived
from the Protein Data Bank, as well as transthyretin - a
protein known for its susceptibility to amyloid transformation
Towards the design of anti-amyloid short peptide helices
A set of short peptide sequences susceptible to fibrillar aggregation produces sequneces capable of arresting elongation of amyloid
fibrils. The "stop" signals are short helices customized for each individual target. Such a helix should exhibit high amphiphilicity,
with differing conditions present on each side (one side should be highly hydrophilic to enable water to interact with the aggregate,
while the other side must retain a local distribution of hydrophobicity which matches that of the terminal portion of the fibril). The
emergence and elongation of fibrillary forms resulting from linear propagation of local hydrophobicity peaks is shown using the
fuzzy oil drop model
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