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.

Mechanism of generation of large(Ti,Nb,V)(C,N)-type precipitates in H13 + Nb tool steel

The characteristics and generation mechanism of（Ti,Nb,V）（C,N） precipitates larger than 2 μm in Nb-containing H13 bar steel were studied. The results show that two types of（Ti,Nb,V）（C,N） phases exist—a Ti-V-rich one and an Nb-rich one—in the form of single or complex precipitates. The sizes of the single Ti-V-rich（Ti,Nb,V）（C,N） precipitates are mostly within 5 to 10 μm, whereas the sizes of the single Nb-rich precipitates are mostly 2–5 μm. The complex precipitates are larger and contain an inner Ti-V-rich layer and an outer Nb-rich layer. The compositional distribution of（Ti,Nb,V）（C,N） is concentrated. The average composition of the single Ti-V-rich phase is（Ti_（0.511）V_（0.356）Nb_（0.133））（CxNy）, whereas that for the single Nb-rich phase is（Ti_（0.061）V_（0.263）Nb_（0.676））（C_xN_y）. The calculation results based on the Scheil–Gulliver model in the Thermo-Calc software combining with the thermal stability experiments show that the large phases precipitate during the solidification process. With the development of solidification, the Ti-V-rich phase precipitates first and becomes homogeneous during the subsequent temperature reduction and heat treatment processes. The Nb-rich phase appears later.

Generation and Evolution of Cavitation Bubbles in Volume Alternate Cavitation(VAC)

Cavitation generation methods have been used in multifarious directions because of their diversity,and numerous studies and discussions have been conducted on cavitation generation methods.This study aims to explore the generating mechanism and evolution law of volume alternate cavitation(VAC).In the VAC,liquid water is placed in an airtight container with a variable volume.As the volume alternately changes,the liquid water inside the container continues to cavitate.Then,the mixture turbulence model and in-cylinder dynamic grid model are adopted to conduct computational fluid dynamics simulation of volume alternate cavitation.In the simulation,the cloud images at seven heights on the central axis are monitored,and the phenomenon and mechanism of height and eccentricity are analyzed in detail.By employing the cavitation flow visualization method,the generating mechanism and evolution law of cavitation are revealed.The synergistic effects of experiments and high-speed camera capturing confirm the correctness of the simulation results.In the experiment,the volume change stroke of the airtight container is set to 20 mm,the volume change frequency is 18 Hz,and the shooting frequency of the high-speed camera is set to 10000 FPS.The experimental results indicate that the position of the cavitation phenomenon has a reasonable law during the whole evolution cycle of the cavitation cloud.Also,the volume alternation cycle corresponds to the generation,development,and collapse stages of cavitation bubbles.

A new type of adiabatic invariants for nonconservative systems of generalized classical mechanics

The perturbations to symmetries and adiabatic invariants for nonconservative systems of generalized classical mechanics axe studied. The exact inwriant in the form of Hojman from a particular Lie symmetry for an undisturbed system of generalized mechanics is given. Based on the concept of high-order adiabatic invaxiant in generalized mechanics, the perturbation to Lie symmetry for the system under the action of small disturbance is investigated, and a new adiabatic invaxiant for the nonconservative system of generalized classical mechanics is obtained, which can be called the Hojman adiabatic invaxiant. An example is also given to illustrate the application of the results.

The spatial characteristic of the short－term and imminent anomalies of waterradonbe┐foreearthquakeinthemainlandofChina

The changes of radon content in underground water(water radon)recorded at about 200 stations in 32 earthquakes occurred in the mainland of China are studied in this paper. The result shows that the spatial distribution of short term and imminent anomalies of water radon before earthquake seems to be mainly related to the active master fault nearby the hypocenter of an earthquake and the earthquake generating mechanism. Finally, some understandings on the mechanism of the aomalies and the imminent earthquake prediction are set forth.

NOETHER’S CONSERVATION LAWS OF HOLONOMIC NONCONSERVATIVE DYNAMICAL SYSTEMS IN GENERALIZED MECHANICS

In the present paper, three kinds of forms for Noether’s conservation laws of hol-onomic nonconservative dynamical systems in generalized mechanics are given.

Symmetry of Hamiltonian and conserved quantity for a system of generalized classical mechanics

This paper focuses on a new symmetry of Hamiltonian and its conserved quantity for a system of generalized classical mechanics. The differential equations of motion of the system are established. The definition and the criterion of the symmetry of Hamiltonian of the system are given. A conserved quantity directly derived from the symmetry of Hamiltonian of the generalized classical mechanical system is given. Since a Hamilton system is a special case of the generalized classical mechanics, the results above are equally applicable to the Hamilton system. The results of the paper are the generalization of a theorem known for the existing nonsingular equivalent Lagrangian. Finally, two examples are given to illustrate the application of the results.

On Form Invariance,Lie Symmetry and Three Kinds of Conserved Quantities of Generalized Lagrange's Equations

In this paper,the form invariance and the Lie symmetry of Lagrange's equations for nonconservativesystem in generalized classical mechanics under the infinitesimal transformations of group are studied,and the Noether'sconserved quantity,the new form conserved quantity,and the Hojman's conserved quantity of system are derived fromthem.Finally,an example is given to illustrate the application of the result.

Noether's theory of generalized linear nonholonomic mechanical systems

By introducing the quasi-symmetry of the infinitesimal transformation of the transformation group Gr, the Noether＇s theorem and the Noether＇s inverse theorem for generalized linear nonholonomic mechanical systems are obtained in a generalized compound derivative space. An example is given to illustrate the application of the result.

RELIABILITY-BASED ANALYSIS AND SYNTHESIS OF MECHANICAL ERROR FOR PATH GENERATING LINKAGES

A reliability-based analysis approach to mechanical error in path generating linkages is pre- sented . The reliability index is taken as a measure for the deviation of the actual path of a coupler point from the desired one. A reliability-based synthesis procedure of the mechanical error for path generating linkages to allocate optimal tolerances and clearances is developed. A four-bar path generating mechanism is considered for numerical illustration.

GENERALIZED THEORY OF NONLINEAR AND UNSTEADY MECHANICS AND APPLICATIONS TO PARTICLE PHYSICS

In this paper we consider that the momentum of a free particle motion withhigh-level speed presenting nonlinear effects may be expanded by using Laurent seriesand then obtain the complete expression of nonlinear and unsteady momentum. These nonlinear and unsieady phenoniena of high-level speed may further expand to the theory of kinematics and it may be determined by Fredholm's integral equation of the first kind. In addition, according to the nonlinear and unsteady momentum obtained the relations of the nonlinear mechanics equations .work and energy, mass and energymay be derived.Finaly .this paper also calculates those experimental results which done in particle physics for mu-mesons u±and fast neutrons n, these results are in agreement with data perfectly.

Modeling the control mechanism for generating the rise-fall patterns in FO contours

The strategy of modeling the control mechanism for generating F0 contour of speech signal is studied in this paper. Based on some dynamic characteristics of vocal cord strain, the complex laryngeal mechanism relative to local F0 regulation is simplified to be a feasible physical model. Furthermore, a model function is deduced as the control mechanism for the generation process of local rise-fall patterns, and two kinds of basic feature patterns result with so called rise-fall commands defined by model parameters. on the logarithmic scale of F0 versus time the local characteristics of an F0 contour are approximated by the sum of these patterns generated by appropriate commands. The experimenial results in analyzing and synthesizing the F0 contours of spoken Chinese utterances indicate that the observed F0 contours can be always approximated well by the model, and a good correlation exists between some model parameters and the transition duration of local F0 rising or falling. The model lays a foundation for Chinese F0 contour synthesis by rule.

Design and analysis of the gripper mechanism based on generalized parallel mechanisms with configurable moving platform

Generalized parallel mechanisms with a configurable moving platform have become popular in the research field of parallel mechanism.This type of gripper mechanism can be applied to grasp large or heavy objects in different environments that are dangerous and complex for humans.This study proposes a family of novel(5+1)degrees of freedom(three translations and two rotations plus an additional grasping motion)gripper mechanisms based on the generalized parallel mechanisms with a configurable moving platform.First,the configurable moving platform,which is a closed loop,is designed for grasping manipulation.The hybrid topological arrangement is determined to improve the stiffness of the manipulator and realize high load-to-weight ratios.A sufficient rule based on Lie group theory is proposed to synthesize the mechanism.TTie hybrid limb structure is also enumerated.A family of novel gripper mechanisms can be assembled through the hybrid limbs by satisfying the rule.Two examples of the gripper mechanisms with and without parallelogram pairs are shown in this study.A kinematic analysis of the example mechanism is presented.The workspace shows that the mechanism possesses high rotational capability.In addition,a stiffiiess analysis is performed.

Gravidynamics,spinodynamics and electrodynamics within the framework of gravitational quantum field theory

By noticing the fact that the charged leptons and quarks in the standard model are chirality-based Dirac spinors since their weak interaction violates maximally parity symmetry though they behave as Dirac fermions in electromagnetic interaction,we show that such a chirality-based Dirac spinor possesses not only electric charge gauge symmetry U(1)but also inhomogeneous spin gauge symmetry WS(1,3)=SP(1,3)?W1,3,which reveals the nature of gravity and spacetime.The gravitational force and spin gauge force are governed by the gauge symmetries W1,3and SP(1,3),respectively,and a biframe spacetime with globally fiat Minkowski spacetime as base spacetime and locally fiat gravigauge spacetime as a fiber is described by the gravigauge field through emergent non-commutative geometry.The gauge-geometry duality and renormalizability in gravitational quantum field theory(GQFT)are carefully discussed.A detailed analysis and systematic investigation on gravidynamics and spinodynamics as well as electrodynamics are carried out within the framework of GQFT.A full discussion on the generalized Dirac equation and Maxwell equation as well as Einstein equation and spin gauge equation is made in biframe spacetime.New effects of gravidynamics as extension of general relativity are particularly analyzed.All dynamic equations of basic fields are demonstrated to preserve the spin gauge covariance and general coordinate covariance due to the spin gauge symmetry and emergent general linear group symmetry GL(1,3,R),so they hold naturally in any spinning reference frame and motional reference frame.

Identifying potential compounds from Bacopa monnieri(brahmi)against coxsackievirus A16 RdRp targeting HFM disease(tomato flu)

Hand,foot,and mouth disease(HFMD),primarily instigated by Coxsackievirus A16(CVA16),poses a serious health concern,necessitating effective therapeutic interventions.The RNA-dependent RNA polymerase(RdRp)of CVA16 emerges as a promising drug target for HFMD treatment.This study presents an in-silico pipeline for the identification of potential RdRp inhibitors against CVA16.A library of 91 natural compounds derived from Bacopa monnieri(brahmi)was virtually screened against the CVA16 RdRp.Here,Bacobitacin D emerged as a promising hit molecule,forming 8 hydrogen bonds including key catalytic site residues(Asp^(238)and Asp^(329))within the RdRp active site.Further,molecular dynamics(MD)simulations and MM/GBSA binding free energy calculations was applied on the top three hits that were selected based on exhaustive docking scores(≤-9.55 kcal/mol).Bacobitacin D exhibited sustainable stability,as evidenced by minimal deviation(RMSD=0.75±0.02 nm)during a 100 ns MD simulation.Importantly,Bacopaside IV exhibited the lowestΔGTOTAL binding free energy(-23.70 kcal/mol),while Bacobitacin D displayed a comparableΔGTOTAL of19.14 kcal/mol.Structural interpretation of the most populated cluster derived from MD simulations showed direct interactions of Bacobitacin D with pivotal catalytic residues,including Asp^(238)and Ser^(289).This comprehensive study confirmed Bacobitacin D as a potent inhibitor of CVA16 RdRp,offering a potential avenue for therapeutic intervention against HFMD.Experimental validation is required to confirm the inhibitory action of Bacobitacin D against HFMD.