Preexisting domain motions underlie protonation-dependent structural transitions of the Ca2+-ATPase

Physical Chemistry Chemical Physics
We have performed microsecond molecular dynamics (MD) simulations to determine the mechanism for protonation-dependent structural transitions of the sarcoplasmic reticulum Ca2+-ATPase (SERCA). Release of two H+ from the transport sites activates SERCA by inducing a structural transition between low (E2) and high (E1) Ca2+-affinity states (E2-to-E1 transition), but the structural mechanism by which transport site deprotonation facilitates this transition is unknown. We performed microsecond all-atom MD simulations to determine the effects of transport site protonation on the structural dynamics of the E2 state in solution. We found that the protonated E2 state has structural characteristics that are similar to those observed in crystal structures of E2. Upon deprotonation, a single Na+ ion rapidly (<10 ns) binds to the transmembrane transport sites and induces a kink in M5, disrupts the M3-M5 interface, and increases the mobility of M3/A-M3 linker. Principal component analysis...  Read more

How does ytterbium chloride interact with DMPC bilayers? A computational and experimental study

Physical Chemistry Chemical Physics
Lanthanide salts have been studied for many years, primarily in Nuclear Magnetic Resonance (NMR) experiments of mixed lipid–protein systems and more recently to study lipid flip-flop in model membrane systems. It is well recognised that lanthanide salts can influence the behaviour of both lipid and protein systems, however a full molecular level description of lipid–lanthanide interactions is still outstanding. Here we present a study of lanthanide–bilayer interactions, using molecular dynamics computer simulations, fluorescence electrostatic potential experiments and nuclear magnetic resonance. Computer simulations reveal the microscopic structure of DMPC lipid bilayers in the presence of Yb3+, and a surprising ability of the membranes to adsorb significant concentrations of Yb3+ without disrupting the overall membrane structure. At concentrations commonly used in NMR experiments, Yb3+ ions bind...  Read more

Tailoring Single Chain Polymer Nanoparticle Thermo-Mechanical Behavior by Cross-link Density

Soft Matter
Single chain polymer nanoparticles (SCPNs) are formed from intrachain cross-linking of a single polymer chain, making SCPN distinct from other polymer nanoparticles for which the shape is predefined before polymerization. The degree of cross-linking in large part determines the internal architecture of the SCPNs and therefore their mechanical and themomechanical properties. Here, we use molecular dynamics (MD) simulations to study thermomechanical behavior of individual SCPNs with different underlying structures by varying the degree of cross-linking and the degree of polymerization. We characterize the particles in terms of shape, structure, glass transition temperature, mobility and stress response to compressive loading. The results indicate that the constituent monomers of SCPNs become less mobile as the degree of cross-linking is increased corresponding to lower diffusivity and higher stress at a given temperature.Read more

Stereoselective binding of agonists to the β2-adrenergic receptor: insights into molecular details and thermodynamics from molecular dynamics simulations

Molecular BioSystems
The β2-adrenergic receptor (β2-AR) is one of the most studied G-protein-coupled receptors. When interacting with ligand molecule, it exhibits the binding characteristic that is strongly dependent on ligand stereoconfiguration. In particular, many experimental and theoretical studies confirmed that stereoisomers of an important β2-AR agonist, fenoterol, are associated with diverse mechanisms of binding and activation of β2-AR. The objective of the present study was to explore the stereoselective binding of fenoterol to β2-AR through the application of the advanced computational methodology based on the enhanced-sampling molecular dynamics simulations and potentials of interactions tailored to investigate the stereorecogniction effects. The results remain in a very good, quantitative agreement with the experimental data (measured in the context of ligand-receptor affinities and their dependence on the temperature) which provides an additional validation for the applied...  Read more

Umbrella Sampling Molecular Dynamics Simulations Reveal Concerted Ion Movement through G-Quadruplex DNA Channels

Physical Chemistry Chemical Physics
We have applied the umbrella sampling (US) method in all-atom molecular dynamics (MD) simulations to obtain potential of mean force (PMF) profiles for ion transport through three representative G-quadruplex DNA channels: [d(TG4T)]4, [d(G3T4G4)]2, and d[G4(T4G4)3]. The US MD results are in excellent agreement with those obtained previously with the adaptive biasing force (ABF) method. We then utilized the unique features in the US MD method to investigate multi-ion effects in [d(G3T4G4)]2 and discovered that the concerted ion movement is crucial for fully explaining the unusual experimental results on ion movement in this particular G-quadruplex system. We anticipate that these modern free-energy methods will be able to aid in silico design of G-quadruplex DNA as ion channels.Read more

Time-dependent Vibrational Spectral Analysis of First Principles Trajectory of Methylamine with Wavelet Transform

Physical Chemistry Chemical Physics
The fluctuation dynamics of amine stretch frequencies, hydrogen bonds, dangling N-D bonds, and orientation profile of amine group of methylamine (MA) are investigated at ambient condition by means of dispersion corrected density functional theory based first principles molecular dynamics (FPMD) simulations. Along with the dynamical properties, various equilibrium properties such as radial distribution functions, spatial distribution function, combined radial and angular distribution functions and hydrogen bonding were also calculated. The instantaneous stretching frequencies of amine groups were obtained by wavelet transform of trajectory obtained from FPMD simulations. The frequency-structure correlation reveals that amine stretching frequency is weakly correlated with nearest nitrogen-deuterium distance. The frequency-frequency correlation function has short time scale of at around 110 fs, and a longer time scale of about 1.15 ps. It is found that, the short time scale originates...  Read more

A coarse-grained model for assisting the investigation of the structure and dynamics of large nucleic acid species by Ion Mobility Spectrometry - Mass Spectrometry

Physical Chemistry Chemical Physics
Ion Mobility Spectrometry-Mass Spectrometry (IMS-MS) is a rapidly emerging tool for the investigation of nucleic acid structure and dynamics. IMS-MS determinations can provide valuable information regarding alternative topologies, folding intermediates, and conformational heterogeneities, which are not readily accessible to other analytical techniques. The leading strategies for data interpretation rely on computational and experimental approaches to correctly assign experimental observations to putative structures. A very effective strategy involves the application of molecular dynamics (MD) simulations to predict the structure of the analyte molecule, calculate its collision cross section (CCS), and then compare this computational value with the corresponding experimental data. While this approach works well for small nucleic acid species, analyzing larger nucleic acids of biological interest is hampered by the computational cost associated with capturing their extensive structure...  Read more

Chemical states of 3d transition metal impurities in liquid lead-bismuth eutectic by first principles calculations

Physical Chemistry Chemical Physics
Steels are easily corroded in liquid lead-bismuth eutectic (LBE) because their components, such as Fe, Cr and Ni, have a high solubility in liquid LBE. To understand the reason for such high solubility of these 3d transition metals, we have performed first-principles molecular dynamics calculations and analyzed pair-correlation functions, electronic densities of states, and Bader charges and volumes of 3d transition metals dissolved in liquid LBE as impurities. The calculations show that the 4s and 3d orbitals of 3d impurity atoms largely interact with the 6p band of LBE, which generates bonding orbitals. We suggest that the high stability of 3d metals in liquid LBE is caused by the interactions of the 4s and 3d orbitals with the 6p band. Spin polarization is induced with V, Cr, Mn, Fe and Co impurity atoms in a similar manner to the Slater-Pauling curve of solid transition metals, which exhibits...  Read more

The role of ion-water interactions in determining the Soret coefficient of LiCl aqueous solutions

Physical Chemistry Chemical Physics
The application of a thermal gradient to an aqueous electrolyte solution induces the Soret effect, and the salt migrates towards hot (thermophilic) or cold regions (thermophobic). Experimental studies of LiCl reported changes in the sign of the Soret coefficient as well as minima in this coefficient at specific salt concentrations and temperatures. At the minimum the thermodiffusive response of the solution is enhanced significantly. We have performed non-equilibrium molecular dynamics simulations of LiCl solutions to quantify the dependence of the sign change and minimum of the Soret coefficient with salt concentration and temperature. Ion isotopic effects are shown to play a secondary role in determining the Soret coefficient, while the diameter of the cation has a significant impact on the coefficient and on the observation of the minimum. Our simulations show that the ordering of water around Li+ plays a key role in determining the Soret coefficient of...  Read more

Phonon Bottleneck and Long-Lived Excited States in π-Conjugated Pyrene Hoop

Physical Chemistry Chemical Physics
In the last decade, recent synthetic advances have launched carbon-based p-conjugated hoops to the forefront of theoretical and experimental investigation not only for their potential use as bottom-up templates for carbon nanotube (CNT) growth, but also for the interesting excitonic effects arising from the cyclic geometry, unique π-system orientation, and unusual electronic interactions and couplings. In particular, cyclic materials based on pyrene, a common component in organic electronics, are popular candidates for the future design of π-conjugated nanorings for optoelectronic applications. Understanding the photophysical response in cyclic oligopyrenes can be achieved using Non-Adiabatic Excited State molecular Dynamics (NA-ESMD). Through NA-ESMD modeling, we reveal details of the nonradiative relaxation processes in the circular pyrene tetramer [4]cyclo-2,7-pyrenylene ([4]CPY) where we find that the strong non-adiabatic coupling combined with the dense manifold of excited...  Read more

In situ Synthesis of Nitrogen-doped Carbon Dots in Interlayer Region of Layered Double Hydroxide with Tunable Quantum Yield

Journal of Materials Chemistry C
Carbon dots (CDs) have drawn considerable research interest due to their fascinating physicochemical property and optical performance. Herein, we report the preparation of nitrogen-doped carbon dots (N-CDs) via an in situ hydrothermal reaction of citric acid (CA) and ethylenediamine (EDA) in the confined two-dimentional gallery of layered double hydroxides (LDH). The resulting N-CDs/LDH material shows long-range ordered structure, with blue-emissive, sheet-like ultrathin N-CDs (~0.62 nm) accommodated in LDH gallery. Specially, the photoluminescence quantum yield (PLQY) can be tuned by adjusting the charge density of LDH host layer, and the maximum value accomplishes 61.63%. This variable performance is attributed to different N-doping contents confirmed by X-ray photoelectron spectroscopy (XPS), elemental analysis and molecular dynamics (MD) simulations. Moreover, N-CDs/LDH composite exhibits temperature-responsive emission under sub-zero conditions (from –150 °C to 0 °C). Its...  Read more

Insight into the Role of Oxygen in Phase-Change Material GeTe

Journal of Materials Chemistry C
Oxygen is widely used to tune the performance of chalcogenide phase-change materials in the usage of phase-Change random access memory (PCRAM) which is considered as the most promising next-generation non-volatile memory. However, the microscopic role of oxygen in the write-erase process, i.e., the reversible phase transition between crystalline and amorphous state of phase-change materials, remains unclear. Using oxygen doped GeTe as an example, this work unravels the role of oxygen at the atomic scale by means of ab initio total energy calculations and ab initio molecular dynamics simulations. Our main finding is that after the amorphization and the subsequent re-crystallization process simulated by ab initio molecular dynamics, oxygen will drag one Ge atom out of its lattice site and both atoms stay in the interstitial region near the Te vacancy that was originally occupied by the oxygen, forming a “dumbbell-like” defect (O-VTe-Ge), which is in sharp...  Read more

Molecular Dynamics Simulations Elucidate Conformational Selection and Induced Fit Mechanisms in the Binding of PD-1 and PD-L1

Molecular BioSystems
Blockage of the interactions between immunologic checkpoint protein PD-1 and its ligand PD-L1 showed efficacy for cancer treatment. X-ray structures have captured static conformational snapshots of PD-1 and revealed that the CC’ loop adopts an open conformation in the apo-protein but turns into a closed form and interacts with PD-L1 in the complex. This structural heterogeneity brings difficulties to the structure-based drug discovery targeting PD-1. To gain insight into the role of the CC’ loop in molecular recognition, we have undertaken a comparative study between the open and closed conformations in apo-PD-1 and the PD-1/PD-L1 complex using molecular dynamics simulations. Results show that the moderate stability of intramolecular hydrogen bonds between SER71 and THR120 allows the CC’ loop to sample both the open and closed states in apo-PD-1. Binding of PD-L1 accelerates the open-to-closed switch and locks the loop in the closed state by four newly formed intermolecular...  Read more

Pegylated and folic acid functionalized carbon nanotube as the pH controlled carrier of doxorubicin. Molecular dynamics analysis of the stability and drug release mechanism

Physical Chemistry Chemical Physics
This work deals with an analysis of the covalent functionalization of a carbon nanotube using polyethylene glycol chains terminated by folic acid fragments. The analysis is focused on the theoretical predictions, using molecular dynamics simulations, of the properties of such constructs as pH controlled carriers of the anticancer drug - doxorubicin. The analyzed systems are expected to hold the doxorubicin in the inner cavity of the carbon nanotube at neutral pH and unload the drug at slightly acidic pH. That property comes from incorporation to the nanotube some dye molecules (p-phenylenediamine or neutral red) which undergo protonation at slightly acidic pH. We found that both dyes lead to formation of a stable, co-absorbed phase of doxorubicin-dye mixture inside the nanotube at physiological pH. At acidic pH we observed a spontaneous release of dyes from the nanotube, leading finally to the state with only doxorubicin encapsulated in the nanotube interior. Thus, the analyzed...  Read more

Corrugated graphene layers for sea water desalination using capacitive deionization

Physical Chemistry Chemical Physics
The effect of the electric field and surface morphology of corrugated graphene (GE) layers on their capacitive deionization process is studied using molecular dynamics simulations. Deionization performances are evaluated in terms of water flow rate and ion adsorption and explained by analysing the water density distribution, radial distribution function and distribution of the ions inside the GE layers. The simulation results reveal that corrugation of GE layers reduces the water flow rate but largely enhances ion adsorption in comparison to the flat GE layers. Such enhancement is mainly due to the adsorption of ions on the GE layers due to the anchoring effect in the regions with wide interlayer distances. Moreover, it reveals that the entrance configuration of the GE layers also has a significant effect on the performance of deionization. Overall, the results from this study will be helpful in designing effective electrode configurations for capacitive deionization.Read more

A Controllable Water Signal Transistor

Physical Chemistry Chemical Physics
We performed molecular dynamics simulations to study the regulating ability of water chains confined in Y-shaped nanochannel. It is shown that a signal at molecular level could be controlled by two other charge-induced signals when water chains confined in a Y-shaped nanochannel, demonstrating promising applications as water signal transistor in nanosignal systems. The mechanism of water signal transistor is similar to the signal logic device. This remarkable controlling ability of water signal is attributed to strong dipole-ordering of water chains in the nanochannel. The controllable water signal process of the Y-shaped nanochannel provides opportunities for future application in the design of molecular-scale signal devices.Read more

Packing energetics determine the folding routes of the RNase-H proteins.

Physical Chemistry Chemical Physics
Comparative studies of proteins from a family have been used to understand factors that determine the folding routes of proteins. It has been conjectured that the folding mechanism of the ribonuclease-H (RNase-H) proteins is determined by the topology of their fold. To test this hypothesis, we computationally studied the folding of four proteins from the RNase-H family which have the overall RNase-H fold, but whose topologies differ in the region termed CORE in E. coli RNase-H. We simulated the folding of these proteins using molecular dynamics (MD) simulations of a coarse-grained structure-based model (SBM) which captures the effects of topology and found that the four proteins had similar folding routes. However, these simulated folding routes do not agree with the folding routes of those RNase-H proteins that have been experimentally characterized. We next simulated the proteins using an SBM which specifically accounts for packing energetics and found that these routes not only...  Read more

The mechanism of aquaporin inhibition by gold compounds elucidated by biophysical and computational methods

Chemical Communications
The inhibition of water and glycerol permeation via human aquaglyceroporin-3 (AQP3) by gold(III) complexes has been studied by stopped-flow spectroscopy and, for the first time, its mechanism has been described using molecular dynamics (MD), combined to density functional theory (DFT) and electrochemical studies. The obtained MD results showed that the most effective gold-based inhibitor, anchored to Cys40 in AQP3, is able to induce shrinkage of the pore preventing glycerol and water permeation. Moreover, good correlation between the Au(III) complex affinity to Cys binding and AQP3 inhibition effects was highlighted, while no influence of the different oxidative character of the complexes could be observed.Read more

Structure, Electrocatalysis and Dynamics of Immobilized Cytochrome PccH and its Microperoxidase

Physical Chemistry Chemical Physics
Geobacter sulfurreducens cells have the ability to exchange electrons with conductive materials, and the periplasmic cytochrome PccH plays an essential role in the direct electrode-to-cell electron transfer in this bacterium. It has atypically low redox potential and unique structural features that differ from those observed in other c-type cytochromes. We report surface enhanced resonance Raman spectroscopic and electrochemical characterization of the immobilized PccH, together with molecular dynamics simulations that allow for the rationalization of experimental observations. Upon attachment to electrodes functionalized with partially or fully hydrophobic self-assembled monolayers, cytochrome PccH displays a distribution of native and non-native heme spin configurations, similar to those observed in horse heart cytochrome c. The native structural and thermodynamic features of PccH are preserved upon attachment on mixed -NH2/-CH3 surfaces, while pure –OH, -NH2 and –COOH surfaces...  Read more

Accelerated evaporation of water on Graphene Oxide

Physical Chemistry Chemical Physics
Using molecular dynamics simulations, we show that the evaporation of nanoscale water on patterned graphene oxide is faster than that on homogeneous graphene oxide. The evaporation rate of water is insensitive to the variation of the oxidation degree on the oxidized region, so long as the water film only distribute on the oxidized region. The evaporation rate drops when water film spread on the unoxidized region. Further analysis showed that, the variation of oxidation degree observably changed the interaction between the outmost water molecules and the solid surface, but the total interaction for the outmost water molecules only had very limited variation due to the correspondingly regulated water-water interaction when water film only distribute on the oxidized region. When the oxidation degree is too low and some unoxidized regions are also covered by water film, the thickness of water film decreases, which extends the life time of hydrogen bonds for the outmost water molecules and...  Read more