5 research outputs found
Conformational Distribution and α‑Helix to β‑Sheet Transition of Human Amylin Fragment Dimer
Experiments suggested that the fibrillation
of the 11–25
fragment (hIAPP(11–25)) of human islet amyloid polypeptide
(hIAPP or amylin) involves the formation of transient α-helical
intermediates, followed by conversion to β-sheet-rich structure.
However, atomic details of α-helical intermediates and the transition
mechanism are mostly unknown. We investigated the structural properties
of the monomer and dimer in atomistic detail by replica exchange molecular
dynamics (REMD) simulations. Transient α-helical monomers and
dimers were both observed in the REMD trajectories. Our calculated
H<sup>α</sup> chemical shifts based on the monomer REMD run
are in agreement with the solution-state NMR experimental observations.
Multiple 300 ns MD simulations at 310 K show that α-helix-to-β-sheet
transition follows two mechanisms: the first involved direct transition
of the random coil part of the helical conformation into antiparallel
β-sheet, and in the second, the α-helical conformation
unfolded and converted into antiparallel β-sheet. In both mechanisms,
the α-helix-to-β-sheet transition occurred via random
coil, and the transition was accompanied by an increase of interpeptide
contacts. In addition, our REMD simulations revealed different temperature
dependencies of helical and β-structures. Comparison with experimental
data suggests that the propensity for hIAPP(11–25) to form
α-helices and amyloid structures is concentration- and temperature-dependent
Temperature-Dependent Conformational Properties of Human Neuronal Calcium Sensor‑1 Protein Revealed by All-Atom Simulations
Neuronal
calcium sensor-1 (NCS-1) protein has orthologues from <i>Saccharomyces
cerevisiae</i> to human with highly conserved
amino acid sequences. NCS-1 is an important factor controlling the
animal’s response to temperature change. This leads us to investigate
the temperature effects on the conformational dynamics of human NCS-1
at 310 and 316 K by all-atom molecular dynamics (MD) simulations and
dynamic community network analysis. Four independent 500 ns MD simulations
show that secondary structure content at 316 K is similar to that
at 310 K, whereas the global protein structure is expanded. Loop 3
(L3) adopts an extended state occuping the hydrophobic crevice, and
the number of suboptimal communication paths between residue D176
and V190 is reduced at 316 K. The dynamic community network analysis
suggests that the interdomain correlation is weakened, and the intradomain
coupling is strengthened at 316 K. The elevated temperature reduces
the number of the salt bridges, especially in C-domain. This study
suggests that the elevated temperature affects the conformational
dynamics of human NCS-1 protein. Comparison of the structural dynamics
of R102Q mutant and Δ176–190 truncated NCS-1 suggests
that the structural and dynamical response of NCS-1 protein to elevated
temperature may be one of its intrinsic functional properties
Interaction Dynamics in Inhibiting the Aggregation of Aβ Peptides by SWCNTs: A Combined Experimental and Coarse-Grained Molecular Dynamic Simulation Study
The aggregation of amyloid-β
peptides (Aβ) is considered as the main possible cause of Alzheimer’s
disease (AD). How to suppress the formation of toxic Aβ aggregates
has been an intensive concern over the past several decades. Increasing
evidence shows that whether carbon nanomaterials can suppress or promote
the aggregation depends on their physicochemical properties. However,
their interaction dynamics remains elusive as amyloid fibrillation
is a complex multistep process. In this paper, we utilized atomic
force microscopy (AFM), electrostatic force microscopy (EFM), ThT/fluorescence
spectroscopy, and cell viability measurements, combined with coarse-grained
molecular dynamic (MD) simulations to study the dynamic interaction
of full length Aβ with single-walled carbon nanotubes (SWCNT).
At the single SWCNTs scale, it is found that the presence of SWCNTs
would result in rapid and spontaneous adsorption of Aβ<sub>1–40</sub> peptides on their surface and stacking into nonfibrillar aggregates
with reduced toxicity, which plays an important role in inhibiting
the formation of toxic oligomers and mature fibrils. Our results provide
new clues for studying the interaction in amyloid/SWCNTs system as
well as for seeking amyloidosis inhibitors with carbon nanomaterials
Effects of the C‑Terminal Tail on the Conformational Dynamics of Human Neuronal Calcium Sensor‑1 Protein
Neuronal
calcium sensor-1 (NCS-1) protein has been implicated in
multiple neuronal functions by binding partners mostly through a largely
exposed hydrophobic crevice (HC). In the absence of a ligand, the
C-terminal tail (loop L3, residues D176 to V190) binds directly to
the HC pocket as a ligand mimetic, occupying the HC and regulating
its conformational stability. A recent experimental study reported
that L3 deletion resulted in global structure destabilization. However,
the influence of C-terminal tail on the conformations of NCS-1 protein
is unclear at the atomic level. In this study, we investigated the
structural properties and the conformational dynamics of wild type
NCS-1 and L3 truncation variant by extensive all-atom molecular dynamics
(MD) simulations. Our cumulative 2 μs MD simulations demonstrated
that L3 deletion increased the structural flexibility of the C-domain
and the distant N-domain. The community network analysis illustrated
that C-terminal tail truncation weakened the interdomain correlation.
Moreover, our data showed that the variant significantly disrupted
the salt bridges network and expanded simultaneously the global structure
and HC. These conformational changes caused by C-terminal tail truncation
may affect the regulation of target interactions. Our study provides
atomic details of the conformational dynamics effects of the C-terminal
tail on human wild type NCS-1
Expanding the Nanoarchitectural Diversity Through Aromatic Di- and Tri-Peptide Coassembly: Nanostructures and Molecular Mechanisms
Molecular
self-assembly is pivotal for the formation of ordered
nanostructures, yet the structural diversity obtained by the use of
a single type of building block is limited. Multicomponent coassembly,
utilized to expand the architectural space, is principally based on
empirical observations rather than rational design. Here we report
large-scale molecular dynamics simulations of the coassembly of diphenylalanine
(FF) and triphenylalanine (FFF) peptides at various mass ratios. Our
simulations show that FF and FFF can co-organize into both canonical
and noncanonical assemblies. Strikingly, toroid nanostructures, which
were rarely observed for the extensively studied FF or FFF, are often
seen in the FF-FFF coassembly simulations and later corroborated by
scanning electron microscopy. Our simulations demonstrate a wide ratio-dependent
variation of nanostructure morphologies including hollow and solid
assemblies, much richer than those formed by each individual moiety.
The hollow-solid structural transformation displays a discontinuous
transition feature, and the toroids appear to be an obligatory intermediate
for the structural transition. Interaction analysis reveals that the
hollow-solid structural transition is mostly dominated by FF–FFF
interactions, while the nanotoroid formation is determined by the
competition between FF–water and FFF–water interactions.
This study provides both structural and mechanistic insights into
the coassembly of FF and FFF peptides, thus offering a molecular basis
for the rational design of bionanomaterials utilizing peptide coassembly