6 research outputs found
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
Human Neuronal Calcium Sensor‑1 Protein Avoids Histidine Residues To Decrease pH Sensitivity
pH is highly regulated in mammalian
central nervous systems. Neuronal
calcium sensor-1 (NCS-1) can interact with numerous target proteins.
Compared to that in
the NCS-1 protein of Caenorhabditis elegans, evolution has avoided the placement of histidine residues at positions
102 and 83 in the NCS-1 protein of humans and Xenopus
laevis, possibly to decrease the conformational sensitivity
to pH gradients in synaptic processes. We used all-atom molecular
dynamics simulations to investigate the effects of amino acid substitutions
between species on human NCS-1 by substituting Arg102 and Ser83 for
histidine at neutral (R102H and S83H) and acidic pHs (R102H<sup>p</sup> and S83H<sup>p</sup>). Our cumulative 5 ÎĽs simulations revealed
that the R102H mutation slightly increases the structural flexibility
of loop L2 and the R102H<sup>p</sup> mutation decreases protein stability.
Community network analysis illustrates that the R102H and S83H mutations
weaken the interdomain and strengthen the intradomain communications.
Secondary structure contents in the S83H and S83H<sup>p</sup> mutants
are similar to those in the wild type, whereas the global structural
stabilities and salt-bridge probabilities decrease. This study highlights
the conformational dynamics effects of the R102H and S83H mutations
on the local structural flexibility and global stability of NCS-1,
whereas protonated histidine decreases the stability of NCS-1. Thus,
histidines at positions 102 and 83 may not be compatible with the
function of NCS-1 whether in the neutral or protonated state
Critical Nucleus Structure and Aggregation Mechanism of the C‑terminal Fragment of Copper–Zinc Superoxide Dismutase Protein
The aggregation of the copper–zinc
superoxide dismutase
(SOD1) protein is linked to familial amyotrophic lateral sclerosis,
a progressive neurodegenerative disease. A recent experimental study
has shown that the <sup>147</sup>GVIGIAQ<sup>153</sup> SOD1 C-terminal
segment not only forms amyloid fibrils in isolation but also accelerates
the aggregation of full-length SOD1, while substitution of isoleucine
at site 149 by proline blocks its fibril formation. Amyloid formation
is a nucleation–polymerization process. In this study, we investigated
the oligomerization and the nucleus structure of this heptapeptide.
By performing extensive replica-exchange molecular dynamics (REMD)
simulations and conventional MD simulations, we found that the GVIGIAQ
hexamers can adopt highly ordered bilayer β-sheets and β-barrels.
In contrast, substitution of I149 by proline significantly reduces
the β-sheet probability and results in the disappearance of
bilayer β-sheet structures and the increase of disordered hexamers.
We identified mixed parallel–antiparallel bilayer β-sheets
in both REMD and conventional MD simulations and provided the conformational
transition from the experimentally observed parallel bilayer sheets
to the mixed parallel–antiparallel bilayer β-sheets.
Our simulations suggest that the critical nucleus consists of six
peptide chains and two additional peptide chains strongly stabilize
this critical nucleus. The stabilized octamer is able to recruit additional
random peptides into the β-sheet. Therefore, our simulations
provide insights into the critical nucleus formation and the smallest
stable nucleus of the <sup>147</sup>GVIGIAQ<sup>153</sup> peptide
R102Q Mutation Shifts the Salt-Bridge Network and Reduces the Structural Flexibility of Human Neuronal Calcium Sensor‑1 Protein
Neuronal
calcium sensor-1 (NCS-1) protein has a variety of different
neuronal functions and interacts with multiple binding partners mostly
through a large solvent-exposed hydrophobic crevice (HC). A single
R102Q mutation in human NCS-1 protein was demonstrated to be associated
with autism disease. Solution NMR study reported that this R102Q mutant
had long-range chemical shift effects on the HC and the C-terminal
tail (L3). To understand the influence of the R102Q mutation on the
HC and L3 of NCS-1, we have investigated the conformational dynamics
and the structural flexibility of wild type (WT) NCS-1 and its R102Q
mutant by conducting extensive all-atom molecular dynamics (MD) simulations.
On the basis of six independent 450 ns MD simulations, we have found
that the R102Q mutation in NCS-1 protein (1) dramatically reduces
the flexibility of loops L2 and L3, (2) facilitates L3 in a more extended
state to occupy the hydrophobic crevice to a larger extent, (3) significantly
affects the intersegment salt bridges, and (4) changes the subspace
of the free energy landscape of NCS-1 protein. Analysis of the salt
bridge network in both WT and the R102Q variant demonstrates that
the R102Q-mutation-induced salt bridge alternations play a critical
role on the reduced flexibility of L2 and L3. These results reveal
the important role of salt bridges on the structural properties of
NCS-1 protein and that R102Q mutation disables the dynamic relocation
of C-terminus, which may block the binding of NCS-1 protein to its
receptors. This study may provide structural insights into the autistic
spectrum disorder associated with R102Q mutation
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 ÎĽs 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
Embedding Metal in the Interface of a p‑n Heterojunction with a Stack Design for Superior Z‑Scheme Photocatalytic Hydrogen Evolution
The construction of a p-n heterojunction
is an efficient strategy to resolve the limited light absorption and
serious charge-carrier recombination in semiconductors and enhance
the photocatalytic activity. However, the promotion effect is greatly
limited by poor interfacial charge transfer efficiency as well as
reduced redox ability of charge carriers. In this work, we demonstrate
that the embedding of metal Pd into the interface between n-type C<sub>3</sub>N<sub>4</sub> and p-type Cu<sub>2</sub>O can further enhance
the interfacial charge transfer and increase the redox ability of
charge carriers through the design of the C<sub>3</sub>N<sub>4</sub>-Pd-Cu<sub>2</sub>O stack nanostructure. The embedded Pd nanocubes
in the stack structure not only trap the charge carriers from the
semiconductors in promoting the electron–hole separation but
also act as a Z-scheme “bridge” in keeping the strong
reduction/oxidation ability of the electrons/holes for surface reactions.
Furthermore, Pd nanocubes also increase the bonding strength between
the two semiconductors. Enabled by this unique design, the hydrogen
evolution achieved is dramatically higher than that of its counterpart
C<sub>3</sub>N<sub>4</sub>-Cu<sub>2</sub>O structure without Pd embedding.
The apparent quantum efficiency (AQE) is 0.9% at 420 nm for the designed
C<sub>3</sub>N<sub>4</sub>-Pd-Cu<sub>2</sub>O. This work highlights
the rational interfacial design of heterojunctions for enhanced photocatalytic
performance