17 research outputs found
Modeling Adsorption, Conformation, and Orientation of the Fis1 Tail Anchor at the Mitochondrial Outer Membrane
Proteins can be targeted to organellar membranes by using a tail anchor (TA), a stretch of hydrophobic amino acids found at the polypeptide carboxyl-terminus. The Fis1 protein (Fis1p), which promotes mitochondrial and peroxisomal division in the yeast Saccharomyces cerevisiae, is targeted to those organelles by its TA. Substantial evidence suggests that Fis1p insertion into the mitochondrial outer membrane can occur without the need for a translocation machinery. However, recent findings raise the possibility that Fis1p insertion into mitochondria might be promoted by a proteinaceous complex. Here, we have performed atomistic and coarse-grained molecular dynamics simulations to analyze the adsorption, conformation, and orientation of the Fis1(TA). Our results support stable insertion at the mitochondrial outer membrane in a monotopic, rather than a bitopic (transmembrane), configuration. Once inserted in the monotopic orientation, unassisted transition to the bitopic orientation is expected to be blocked by the highly charged nature of the TA carboxyl-terminus and by the Fis1p cytosolic domain. Our results are consistent with a model in which Fis1p does not require a translocation machinery for insertion at mitochondria
Modeling Adsorption, Conformation, and Orientation of the Fis1 Tail Anchor at the Mitochondrial Outer Membrane
Proteins can be targeted to organellar membranes by using a tail anchor (TA), a stretch of hydrophobic amino acids found at the polypeptide carboxyl-terminus. The Fis1 protein (Fis1p), which promotes mitochondrial and peroxisomal division in the yeast Saccharomyces cerevisiae, is targeted to those organelles by its TA. Substantial evidence suggests that Fis1p insertion into the mitochondrial outer membrane can occur without the need for a translocation machinery. However, recent findings raise the possibility that Fis1p insertion into mitochondria might be promoted by a proteinaceous complex. Here, we have performed atomistic and coarse-grained molecular dynamics simulations to analyze the adsorption, conformation, and orientation of the Fis1(TA). Our results support stable insertion at the mitochondrial outer membrane in a monotopic, rather than a bitopic (transmembrane), configuration. Once inserted in the monotopic orientation, unassisted transition to the bitopic orientation is expected to be blocked by the highly charged nature of the TA carboxyl-terminus and by the Fis1p cytosolic domain. Our results are consistent with a model in which Fis1p does not require a translocation machinery for insertion at mitochondria
Role of Hydrophobic/Aromatic Residues on the Stability of Double-Wall β‑Sheet Structures Formed by a Triblock Peptide
Bioinspired
self-assembling peptides serve as powerful building
blocks in the manufacturing of nanomaterials with tailored features.
Because of their ease of synthesis, biocompatibility, and tunable
activity, this emerging branch of biomolecules has become very popular.
The triblock peptide architecture designed by the Hartgerink group
is a versatile system that allows control over its assembly and has
been shown to demonstrate tunable bioactivity. Three main forces,
Coulomb repulsion, hydrogen bonding and hydrophobicity act together
to guide the triblock peptides’ assembly into one-dimensional
objects and hydrogels. It was shown previously that both the nanofiber
morphology (e.g., intersheet spacing, formation of antiparallel/parallel
β-sheets) and hydrogel rheology strictly depend on the choice
of the core residue where the triblock peptide fibers with aromatic
cores in general form shorter fibers and yield poor hydrogels with
respect to the ones with aliphatic cores. However, an elaborate understanding
of the molecular reasons behind these changes remained unclear. In
this study, by using carefully designed computer based free energy
calculations, we analyzed the influence of the core residue on the
formation of double-wall fibers and single-wall β-sheets. Our
results demonstrate that the aromatic substitution impairs the fiber
cores and this impairment is mainly associated with a reduced hydrophobic
character of the aromatic side chains. Such weakening is most obvious
in tryptophan containing peptides where the fiber core absorbs a significant
amount of water. We also show that the ability of tyrosine to form
side chain hydrogen bonds plays an indispensable role in the fiber
stability. As opposed to the impairment of the fiber cores, single-wall
β-sheets with aromatic faces become more stable compared to
the ones with aliphatic faces suggesting that the choice of the core
residue can also affect the underlying assembly mechanism. We also
provide an in-depth comparison of competing structures (zero-dimensional
aggregates, short and long fibers) in the triblock peptides’
assembly and show that by adjusting the length of the terminal blocks,
the fiber growth can be turned on or off while keeping the nanofiber
morphology intact
Assembly of Triblock Amphiphilic Peptides into One-Dimensional Aggregates and Network Formation
Peptide
assembly plays a key role in both neurological diseases
and development of novel biomaterials with well-defined nanostructures.
Synthetic model peptides provide a unique platform to explore the
role of intermolecular interactions in the assembly process. A triblock
peptide architecture designed by the Hartgerink group is a versatile
system which relies on Coulomb interactions, hydrogen bonding, and
hydrophobicity to guide these peptides’ assembly at three different
length scales: β-sheets, double-wall ribbon-like aggregates,
and finally a highly porous network structure which can support gels
with ≤1% by weight peptide concentration. In this study, by
using molecular dynamics simulations of a structure based implicit
solvent coarse grained model, we analyzed this hierarchical assembly
process. Parametrization of our CG model is based on multiple-state
points from atomistic simulations, which enables this model to represent
the conformational adaptability of the triblock peptide molecule based
on the surrounding medium. Our results indicate that emergence of
the double-wall β-sheet packing mechanism, proposed in light
of the experimental evidence, strongly depends on the subtle balance
of the intermolecular forces. We demonstrate that, even though backbone
hydrogen bonding dominates the early nucleation stages, depending
on the strength of the hydrophobic and Coulomb forces, alternative
structures such as zero-dimensional aggregates with two β-sheets
oriented orthogonally (which we refer to as a cross-packed structure)
and β-sheets with misoriented hydrophobic side chains are also
feasible. We discuss the implications of these competing structures
for the three different length scales of assembly by systematically
investigating the influence of density, counterion valency, and hydrophobicity
The effects of preoperative non-invasive cardiac tests on delay to surgery and subsequent mortality in elderly patients with hip fracture
OBJECTIVE: To investigate the effects of preoperative cardiac tests on the surgical treatment plan and subsequent effects on mortality in elderly patients with hip fracture