Exploring unbinding mechanism of drugs from SERT via molecular dynamics simulation and its implication in antidepressants

The human serotonin transporter(SERT)terminates neurotransmission by removing serotonin from the synaptic cleft,which is an essential process that plays an important role in depression.In addition to natural substrate serotonin,SERT is also the target of the abused drug cocaine and,clinically used antidepressants,escitalopram,and paroxetine.To date,few studies have attempted to investigate the unbinding mechanism underlying the orthosteric and allosteric modulation of SERT.In this article,the conserved property of the orthosteric and allosteric sites(S1 and S2)of SERT was revealed by combining the high resolutions of x-ray crystal structures and molecular dynamics(MD)simulations.The residues Tyr95 and Ser438 located within the S1 site,and Arg104 located within the S2 site in SERT illustrate conserved interactions(hydrogen bonds and hydrophobic interactions),as responses to selective serotonin reuptake inhibitors.Van der Waals interactions were keys to designing effective drugs inhibiting SERT and further,electrostatic interactions highlighted escitalopram as a potent antidepressant.We found that cocaine,escitalopram,and paroxetine,whether the S1 site or the S2 site,were more competitive.According to this potential of mean force(PMF)simulations,the new insights reveal the principles of competitive inhibitors that lengths of trails from central SERT to an opening were~18A for serotonin and~22 A for the above-mentioned three drugs.Furthermore,the distance between the natural substrate serotonin and cocaine(or escitalopram)at the allosteric site was~3A.Thus,it can be inferred that the potent antidepressants tended to bind at deeper positions of the S1 or the S2 site of SERT in comparison to the substrate.Continuing exploring the processes of unbinding four ligands against the two target pockets of SERT,this study observed a broad pathway in which serotonin,cocaine,escitalopram(at the S1 site),and paroxetine all were pulled out to an opening between MT1b and MT6a,which may be helpful to understand the dissociation mechanism of antidepressants.

Mechanical property and deformation mechanism of gold nanowire with non-uniform distribution of twinned boundaries:A molecular dynamics simulation study

The mechanical property and deformation mechanism of twinned gold nanowire with non-uniform distribution of twinned boundaries(TBs)are studied by the molecular dynamics(MD)method.It is found that the twin boundary spacing(TBS)has a great effect on the strength and plasticity of the nanowires with uniform distribution of TBs.And the strength enhances with the decrease of TBS,while its plasticity declines.For the nanowires with non-uniform distribution of TBs,the differences in distribution among different TBSs have little effect on the Young's modulus or strength,and the compromise in strength appears.But the differences have a remarkable effect on the plasticity of twinned gold nanowire.The twinned gold nanowire with higher local symmetry ratio has better plasticity.The initial dislocations always form in the largest TBS and the fracture always appears at or near the twin boundaries adjacent to the smallest TBS.Some simulation results are consistent with the experimental results.

Theoretical studies and molecular dynamics simulations on ion transport properties in nanochannels and nanopores

Control of ion transport and fluid flow through nanofluidic devices is of primary importance for energy storage and conversion, drug delivery and a wide range of biological processes. Recent development of nanotechnology, synthesis techniques, purification technologies, and experiment have led to rapid advances in simulation and modeling studies on ion transport properties. In this review, the applications of Poisson-Nernst-Plank （PNP） equations in analyzing transport properties are presented. The molecular dynamics （MD） studies of transport properties of ion and fluidic flow through nanofluidic devices are reported as well.

Transport Properties of Fluids in Micropores by Molecular Dynamics Simulation

The transport properties of fluid argon in micropores, i.e. diffusivity and viscosity, were studied by molecular dynamics simulations. The effects of pore width, temperature and density on diffusivity and viscosity were analyzed in micropores with pore widths from 0.8 to 4.0 nm. The results show that the diffusivity in micropores is much lower than the bulk diffusivity, and it decreases as the pore width decreases; but the viscosity in micropores is significantly larger than the bulk one, and it increases sharply in narrow micropores. The diffusivity in channel parallel direction is obviously larger than that in channel perpendicular direction. The temperature and density are important factors that obviously affect diffusivity and viscosity in micropores.

Investigation on the Mechanical Properties of Polycrystalline Mg Using Molecular Dynamics Simulation

Magnesium(Mg)and its composites have been widely used in different fields,but the mechanical properties and deformation mechanisms of polycrystalline Mg(polyMg)at the atomic scale are poorly understood.In this paper,the effects of grain size,temperature,and strain rate on the tensile properties of polyMg are explored and discussed by theMolecular dynamics(MD)simulation method.The calculated results showed that there exists a critical grain size of 10 nm for the mechanical properties of polyMg.The flow stress decreases with the increase of grain size if the average grain size is larger than 10 nm,which shows the Hall-Petch effect,and the deformation mechanism of large grain-sized polyMg is mainly dominated by the movement of dislocations.When the average grain size is less than 10 nm,it shows the reverse Hall-Petch effect that the flow stress decreases with the decrease of grain size,and the deformation mode of polyMg with small grain-size is the movement and deformation of atoms at the grain boundary.Due to the more active motion of atoms as the system temperature increases,the material can easily reach the plastic stage under tensile loading,and the mechanical properties of polyMg decrease at high temperatures.The strain rate has a hardening effect on the properties of composite.Based on our calculated results,it can provide theoretical guidance for the applications of Mg metal and Mg matrix composites.

Quantifying spectral thermal transport properties in framework of molecular dynamics simulations:a comprehensive review

Over the past few decades,significant progress has been made in micro-and nanoscale heat transfer.Numerous computational methods have been developed to quantitatively characterize the thermal transport in bulk materials and across the interfaces,which benefit the thermal management design in microelectronics and energy conversion in thermoelectrics largely.In this paper,the methods and studies on quantifying thermal transport properties using molecular dynamics simulations are comprehensively reviewed.Two classical methods based on molecular dynamics simulations are first introduced,i.e.,equilibrium molecular dynamics and nonequilibrium molecular dynamics,to calculate the thermal transport properties in bulk materials and across the interfaces.The spectroscopy methods are then reviewed,which are developed in the framework of equilibrium molecular dynamics(i.e.,time domain normal mode analysis,spectral energy density,Green-Kubo modal analysis) and methods proposed based on the nonequilibrium molecular dynamics(i.e.,time domain direct decompose method,frequency domain direct decompose method and spectral heat flux method).In the subsequent section,the calculations of spectral thermal conductivities using these computational methods in various systems are presented,including simple crystals,low-dimensional materials,complex materials and nanostructures.Following that,spectral thermal transport across the interfacial systems is discussed,which includes solid/solid interfaces,solid/solid interfaces with interfacial engineering and solid/liquid interfaces.Some fundamental challenges in molecular dynamics simulations,such as including quantum effects and quantifying the anharmonic contributions,are discussed as well.Finally,some open problems on spectroscopy thermal transport properties in the framework of molecular dynamics simulations are given in the summary.

Understanding the interfacial properties of benzene alkylation with 1-dodecene catalyzed by immobilized chloroaluminate ionic liquids using molecular dynamics simulation

Benzene alkylation catalyzed by immobilized ionic liquids(ILs)on solid carriers is considered as a heterogeneous reaction,in which the interfacial properties play an important role.Hence,the interfacial characteristics between benzene/1-dodecene mixture and immobilized chloroaluminate ILs with different alkyl chain length on the silica substrate were investigated by molecular dynamics simulation.The grafted ILs can obviously promote the enrichment of benzene near the interface,leading to a higher ratio of benzene to dodecene,and the interfacial width increases slightly with increased alkyl chain of grafted cations.At the same time,the grafted cations can also enhance the benzene diffusion and suppress the dodecene diffusion at the interface,which probably helps to inhibit the inactivation of catalysts.This work provides deeply insights into the rational design of novel immo-bilized ILs catalysts for the benzene alkylation.

Molecular dynamics simulation studies of transmembrane transport of chemical components in Chinese herbs and the function of platycodin D in a biological membrane

Objective:To study the transmembrane transport of chemical components of Chinese herbs and to explore the function of platycodin D (PD) on biomembranes.Methods:Interaction between PD and the dipalmitoylphosphatidylcholine (DPPC) bilayer was reproduced by molecular dynamics simulation with the Martini force field.A model validation and methodological study were first performed,and were based on simulation investigations of transmembrane transport for three herbal compounds with distinct hydrophilic properties.Results:PD increased the mobility of the DPPC bilayer since its aglycone strongly interacted with the hydrophobic layer,which broke the structure of the gate layer,and weakened the ordered performance of hydrophobic tails.Conclusion:The Martini force field was successfully applied to the study of the interaction between herbal compounds and a biological membrane.By combining the dynamics equilibrium morphology,the distribution of drugs inside and outside the biomembrane,and the interaction sites of drugs on the DPPC bilayer,factors influencing transmembrane transport of drugs were elucidated and the function of platycodin D in a biological membrane was reproduced.

Molecular Simulation on Transport Properties of Confined Water

The diffusivity and viscosity of water confined in micropores were studied by molecular dynamics simulations. The effects of pore width and density were analyzed at pore widths from 0.9 to 2.6 nm. The diffusivity in micropores is lower than that of the bulk, and it decreases as pore width decreases and as density increases. But the viscosity in micropores is much larger than that of the bulk, and it increases as pore width decreases and as density increases. The diffusivity in channel parallel direction is obviously larger than that in channel perpendicular directions.

Effects of Strain Rate,Temperature and Grain Size on the Mechanical Properties and Microstructure Evolutions of Polycrystalline Nickel Nanowires:A Molecular Dynamics Simulation

Through molecular dynamics（MD） simulation, the dependencies of temperature, grain size and strain rate on the mechanical properties were studied. The simulation results demonstrated that the strain rate from 0.05 to 2 ns–1 affected the Young＇s modulus of nickel nanowires slightly, whereas the yield stress increased. The Young＇s modulus decreased approximately linearly; however, the yield stress firstly increased and subsequently dropped as the temperature increased. The Young＇s modulus and yield stress increased as the mean grain size increased from 2.66 to 6.72 nm. Moreover, certain efforts have been made in the microstructure evolution with mechanical properties association under uniaxial tension. Certain phenomena such as the formation of twin structures, which were found in nanowires with larger grain size at higher strain rate and lower temperature, as well as the movement of grain boundaries and dislocation, were detected and discussed in detail. The results demonstrated that the plastic deformation was mainly accommodated by the motion of grain boundaries for smaller grain size. However, for larger grain size, the formations of stacking faults and twins were the main mechanisms of plastic deformation in the polycrystalline nickel nanowire.

Using thermodynamic parameters to study self-healing and interface properties of crumb rubber modified asphalt based on molecular dynamics simulation

The thermodynamic property of asphalt binder is changed by the addition of crumb rubber,which in turn influences the self-healing property as well as the cohesion and adhesion within the asphalt-aggregate system.This study investigated the self-healing and interface properties of crumb rubber modified asphalt(CRMA)using thermodynamic parameters based on the molecular simulation approach.The molecular models of CRMA were built with representative structures of the virgin asphalt and the crumb rubber.The aggregate was represented by SiO2 and Al2O3 crystals.The selfhealing capability was evaluated with the thermodynamic parameter wetting time,work of cohesion and diffusivity.The interface properties were evaluated by characterizing the adhesion capability,the debonding potential and the moisture susceptibility of the asphalt-aggregate interface.The self-healing capability of CRMA is found to decrease as the rubber content increases.The asphalt-Al2O3 interface with higher rubber content has stronger adhesion and moisture stability.But the influence of crumb rubber on the interfacial properties of asphalt-SiO2 interface has no statistical significance.Comparing with the interfacial properties of the asphalt-SiO2 interface,the asphalt-Al2O3 interface is found to have a stronger adhesion but a worse moisture susceptibility for its enormous thermodynamic potential for water to displace the asphalt binder.

Molecular dynamics study on the dependence of thermal conductivity on size and strain in GaN nanofilms

The thermal conductivity of GaN nanofilm is simulated by using the molecular dynamics(MD)method to explore the influence of the nanofilm thickness and the pre-strain field under different temperatures.It is demonstrated that the thermal conductivity of GaN nanofilm increases with the increase of nanofilm thickness,while decreases with the increase of temperature.Meanwhile,the thermal conductivity of strained GaN nanofilms is weakened with increasing the tensile strain.The film thickness and environment temperature can affect the strain effect on the thermal conductivity of GaN nanofilms.In addition,the analysis of phonon properties of GaN nanofilm shows that the phonon dispersion and density of states of GaN nanofilms can be significantly modified by the film thickness and strain.The results in this work can provide the theoretical supports for regulating the thermal properties of GaN nanofilm through tailoring the geometric size and strain engineering.

Thermal wave propagation in graphene studied by molecular dynamics simulations

The transient heat conduction in both armchair and zigzag-edged graphene ribbons pulsed by local heating with a duration of 1 ps was studied using nonequilibrium molecular dynamics simulations. The results show that the heat pulse excites two waves which indicates non-Fourier heat conduction. One of the two waves is a sound wave(first sound), which has macroscopic momentum and propagates at the speed of sound. The other is a thermal wave(second sound), whose propagation speed is 1=ffiffi3pof the sound velocity. The sound wave excited by the heat pulse is a longitudinal wave, whose energy is only transported in the longitudinal direction. The thermal wave excited by the heat pulse is generated by transverse lattice vibrations, with the energy only having the transverse component. The observed anisotropy of the transient heat conduction suggests that the system is in a non-equilibrium state during propagation of the heat pulse. Further statistical analyses show that the displacement of the heat pulse energy is related to the time as hr2 i / t1:80, which implies that heat transport is ballistic-diffusive transport in graphene. The higher proportion of the ballistic transport will lead to stronger heat waves. At the crest of the thermal wave, energy is transported ballistically, while in the diffusive region and during attenuation of the thermal wave,the energy is transported diffusively.

Evolution of misfit dislocation network and tensile properties in Ni-based superalloys:a molecular dynamics simulation

The structural evolution of dislocation network is closely related to ' rafting and tensile properties.In this work,the effects of strain rate and temperature on the structural evolution of interface dislocation network in Ni-based superalloys are studied by molecular dynamics simulations.The correlation between the evolution of dislocation network and tensile properties is also explored.The results indicate that the dislocation network shows different degrees of deformation and damage at various strain rates and temperatures.The ' rafting depends on the damage structure of dislocation network at various strain rates and temperatures.Moreover,the tensile properties of interface in Ni-based superalloys are closely related to the evolution of dislocation network and dislocation motion mechanisms.

Transport properties of warm and hot dense iron from orbital free and corrected Yukawa potential molecular dynamics

The equation of states,diffusions,and viscosities of strongly coupled Fe at 80 and 240 eV with densities from 1.6 to 40 g/cm^(3) are studied by orbital-free molecular dynamics,classical molecular dynamics with a corrected Yukawa potential and compared with the results from average atom model.A new local pseudopotential is generated for orbital free calculations.For low densities,the Yukawa model captures the correct ionic interaction behavior around the first peak of the radial distribution function(RDF),thus it gives correct RDFs and transport coefficients.For higher densities,the scaled transformation of the Yukawa potential or adding a short range repulsion part to the Yukawa potential can give correct RDFs and transport coefficients.The corrected potentials are further validated by the force matching method.

Molecular Dynamics Simulation Studies on the Micromorphology and Proton Transport of Nafion/Ti_(3)C_(2)T_(x) Composite Membrane

The perfluorosulfonic acid(PFSA) membrane doped with two-dimensional conductive filler Ti_(3)C_(2)T_(x) is a fuel cell proton exchange membrane with high application potential. Experimental studies showed that the proton conductivity of Nafion/Ti_(3)C_(2)T_(x) composite membrane is improved significantly compared with that in pure Nafion. However, the microscopic mechanism of doping on the enhancement of membrane performance is remain unclear now. In this work, molecular dynamics simulation was used to investigate the microscopic morphology and proton transport behaviors of Nafion/Ti_(3)C_(2)T_(x) composite membrane at the molecular level. The results shown that there were significant differences about the diffusion kinetics of water molecules and hydroxium ions in Nafion/Ti_(3)C_(2)T_(x) at low and high hydration levels in the nanoscale region.With the increase of water content, Ti_(3)C_(2)T_(x) in membrane was gradually surrounded by ambient water molecules to form a hydration layer, and forming a relatively continuous proton transport channel between Nafion polymer and Ti_(3)C_(2)T_(x) monomer. The continuous proton transport channel could increase the number of binding sites of proton and thus achieving high proton conductivity and high mobility of water molecules at higher hydration level. The current work can provide a theoretical guidance for designing new type of Nafion composite membranes.

Molecular dynamics simulations of mechanical properties of epoxy-amine:Cross-linker type and degree of conversion effects

Molecular dynamics(MD)simulations are conducted to study the thermo-mechanical properties of a family of thermosetting epoxy-amines.The crosslinked epoxy resin EPON862 with a series of cross-linkers is built and simulated under the polymer consistent force field(PCFF).Three types of curing agents(rigidity1,3-phenylenediamine(1,3-P),4,4-diaminodiphenylmethane(DDM),and phenol-formaldehyde-ethylenediamine(PFE))with different numbers of active sites are selected in the simulations.We focus on the effects of the cross-linkers on thermo-mechanical properties such as density,glass transition temperature(T_(g)),elastic constants,and strength.Our simulations show a significant increase in the Tg,Young’s modulus and yield stress with the increase in the degree of conversion.The simulation results reveal that the mechanical properties of thermosetting polymers are strongly dependent on the molecular structures of the cross-linker and network topological properties,such as end-to-end distance,crosslinking density and degree of conversion.

Tunable Anisotropic Lattice Thermal Conductivity in One-Dimensional Superlattices from Molecular Dynamics Simulations

Engineering nanostructured superlattices provides an effective solution toward the realization of high-performance thermoelectric device and thermal management materials,where the anisotropic thermal conductivity is critical for designing orientation-dependent thermal devices.Herein,the lattice thermal conductivity anisotropy of Al/Ag superlattices as one typical example of superlattice materials is investigated utilizing non-equilibrium molecular dynamics simulations.The cross-plane and in-plane lattice thermal conductivities of one-dimensional superlattices are in the ranges of 0.5–3.2 W/(m·K)and 1.8–5.1 W/(m·K)at different period lengths,respectively,both of which are smaller than those of bulk materials.More specifically,the cross-plane lattice thermal conductivity of superlattices increases with the period length,while the in-plane phonon thermal conductivity first increases and then trends to convergence,resulting in the non-monotonic thermal anisotropy value.To further reveal the microscopic phonon transport mechanism,the interfacial phonon thermal resistance,density of states and spectral phonon transmission coefficient including anharmonic phonon properties under different period lengths are calculated.Our results can be helpful for understanding phonon transport in low-dimensional materials and provide guidance for optimizing the thermal conductivity anisotropy of superlattice materials in the application ranging from thermoelectric devices to thermal management in micro/nano systems.

Mechanical properties of Fe-based amorphous–crystalline composite: a molecular dynamics simulation and experimental study

A new Fe-based amorphous–crystalline composite without non-metallic elements, Fe_(55)Cr_(15)Mo_(15)Ni_(10)W_(5), was prepared by melt-spinning. The formation ability and structure information were investigated by X-ray diffractometer(XRD), energy-dispersive spectrometer(EDS) and scanning electron microscope(SEM). The mechanical properties of the amorphous–crystalline composite were investigated by nanoindentation. A molecular dynamics simulation study was performed to simulate the formation of Fe_(55)Cr_(15)Mo_(15)Ni_(10)W_(5) amorphous alloy. The mechanical properties were obtained by compression simulations simultaneously. The results indicate that the Fe_(55)Cr_(15)Mo_(15)Ni_(10)W_(5) ribbon is an amorphous–crystalline composite structure with good ductility, and the hardness of the amorphous–crystalline composite is about 75%higher than that of master ingot. The simulation mechanical properties are in good agreement with the results of nanoindentation at the nanoscale.

Molecular dynamics simulations on the wet/dry self-latching and electric fields triggered wet/dry transitions between nanosheets:A non-volatile memory nanostructure

We design a nanostructure composing of two nanoscale graphene sheets parallelly immersed in water.Using molecular dynamics simulations,we demonstrate that the wet/dry state between the graphene sheets can be self-latched;moreover,the wet→dry/dry→wet transition takes place when applying an external electric field perpendicular/parallel to the graphene sheets(E;/E;).This structure works like a flash memory device(a non-volatile memory):the stored information(wet and dry states)of the system can be kept spontaneously,and can also be rewritten by external electric fields.On the one hand,when the distance between the two nanosheets is close to a certain distance,the free energy barriers for the transitions dry→wet and wet→dry can be quite large.As a result,the wet and dry states are self-latched.On the other hand,an E;and an E;will respectively increase and decrease the free energy of the water located in-between the two nanosheets.Consequently,the wet→dry and dry→wet transitions are observed.Our results may be useful for designing novel information memory devices.