13 research outputs found
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
Conformation and Aggregation of LKα14 Peptide in Bulk Water and at the Air/Water Interface
Historically, the protein folding
problem has mainly been associated
with understanding the relationship between amino acid sequence and
structure. However, it is known that both the conformation of individual
molecules and their aggregation strongly depend on the environmental
conditions. Here, we study the aggregation behavior of the model peptide
LKα14 (with amino acid sequence LKKÂLLKÂLLKÂKLLÂKL)
in bulk water and at the air/water interface. We start by a quantitative
analysis of the conformational space of a single LKα14 in bulk
water. Next, in order to analyze the aggregation tendency of LKα14,
by using the umbrella sampling technique we calculate the potential
of mean force for pulling a single peptide from an n-molecule aggregate.
In agreement with the experimental results, our calculations yield
the optimal aggregate size as four. This equilibrium state is achieved
by two opposing forces: Coulomb repulsion between the lysine side
chains and the reduction of solvent accessible hydrophobic surface
area upon aggregation. At the vacuum/water interface, however, even
dimers of LKα14 become marginally stable, and any larger aggregate
falls apart instantaneously. Our results indicate that even though
the interface is highly influential in stabilizing the α-helix
conformation for a single molecule, it significantly reduces the attraction
between two LKα14 peptides, along with their aggregation tendency
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
Conformation and Aggregation of LKα14 Peptide in Bulk Water and at the Air/Water Interface
Historically, the protein folding
problem has mainly been associated
with understanding the relationship between amino acid sequence and
structure. However, it is known that both the conformation of individual
molecules and their aggregation strongly depend on the environmental
conditions. Here, we study the aggregation behavior of the model peptide
LKα14 (with amino acid sequence LKKÂLLKÂLLKÂKLLÂKL)
in bulk water and at the air/water interface. We start by a quantitative
analysis of the conformational space of a single LKα14 in bulk
water. Next, in order to analyze the aggregation tendency of LKα14,
by using the umbrella sampling technique we calculate the potential
of mean force for pulling a single peptide from an n-molecule aggregate.
In agreement with the experimental results, our calculations yield
the optimal aggregate size as four. This equilibrium state is achieved
by two opposing forces: Coulomb repulsion between the lysine side
chains and the reduction of solvent accessible hydrophobic surface
area upon aggregation. At the vacuum/water interface, however, even
dimers of LKα14 become marginally stable, and any larger aggregate
falls apart instantaneously. Our results indicate that even though
the interface is highly influential in stabilizing the α-helix
conformation for a single molecule, it significantly reduces the attraction
between two LKα14 peptides, along with their aggregation tendency
Adsorption, Folding, and Packing of an Amphiphilic Peptide at the Air/Water Interface
Peptide oligomers play an essential role as model compounds
for identifying key motifs in protein structure formation and protein
aggregation. Here, we present our results, based on extensive molecular
dynamics simulations, on adsorption, folding, and packing within a
surface monolayer of an amphiphilic peptide at the air/water interface.
Experimental results suggest that these molecules spontaneously form
ordered monolayers at the interface, adopting a β-hairpin-like
structure within the surface layer. Our results reveal that the β-hairpin
structure can be observed both in bulk and at the air/water interface.
However, the presence of an interface leads to ideal partitioning
of the hydrophobic and hydrophilic residues, and therefore reduces
the conformational space for the molecule and increases the stability
of the hairpin structure. We obtained the adsorption free energy of
a single β-hairpin at the air/water interface, and analyzed
the enthalpic and entropic contributions. The adsorption process is
favored by two main factors: (1) Free-energy reduction due to desolvation
of the hydrophobic side chains of the peptide and release of the water
molecules which form a cage around these hydrophobic groups in bulk
water. (2) Reduction of the total air/water contact area at the interface
upon adsorption of the peptide amphiphile. By performing mutations
on the original molecule, we demonstrated the relative role of key
design features of the peptide. Finally, by analyzing the potential
of mean force among two peptides at the interface, we investigated
possible packing mechanisms for these molecules within the surface
monolayer
PMF results comparing the separation of a LK dimer in bulk water for the cases where lysine residues are positively charged, lysine residues are neutral and the leucine residues are in silico mutated to alanine residues.
<p>The curves are shifted so that the maximum points are zero. The distance refers to the distance between the center of mass of backbone atoms of the peptides. For the mutated AK dimer, when the peptides are in contact they maintain their helical structures. However when they are separated or when they make a loose contact the <i>α</i>-helical structure is not conserved.</p
Time evolution of secondary structure for LK (left) and EALA (right) when isolated in bulk water.
<p>Snapshots depicting various conformations adopted by these molecules (A and B), DSSP analysis of secondary structure (C and D), SASA for hydrophobic sidechains (h-SASA), number of intra-peptide backbone hydrogen bonds (H-bond) and short-range Coulomb interaction energies (Coul-SR) between the charged groups (E and F) are given for both of the molecules. See <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004328#sec008" target="_blank">Methods</a> section for the color coding and representation of peptides in A and B.</p
Time evolution of the secondary structure of a dimer of LK (left) and EALA (right) at the vacuum/water interface.
<p>Typical snapshots when the peptides are associated at the interface (A and B), DSSP structural analysis (C and D), angle between the helix axis for the peptides and center-to-center distance (E and F), the h-SASA for each peptide along with the buried SASA for the whole peptide, the inter and intra molecular short-range Coulomb energies and the number of inter- and intra-molecular hydrogen bonds (G and H) are shown in figure.</p
Folding and association of a pair of LK (left) and EALA (right) peptides in bulk water.
<p>Snapshots illustrating the aggregation process (A and B), DSSP secondary structure analysis (C and D), SASA, short range Coulombic interaction energies between the charged groups and the number of intra and inter-peptide backbone hydrogen bonds (E and F) are displayed as a function of simulation time. Association of peptides take place at 180 ns for LK and 300 ns for EALA, which can be observed via the sharp drop in SASA.</p
Three separate contributions govern the dynamic conformational equilibrium of an amphiphilic peptide.
<p>The folding of the individual molecule in solution (A); the partitioning of hydrophobic/hydrophilic residues induced by macroscopic interfaces (B) or molecular interfaces upon aggregation (C). Combinations of these effects (connecting arcs D, E and F) determine the preferred secondary structure in a given environment.</p