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.

Identification of key residues in protein functional movements by using molecular dynamics simulations combined with a perturbation-response scanning method

The realization of protein functional movement is usually accompanied by specific conformational changes,and there exist some key residues that mediate and control the functional motions of proteins in the allosteric process.In the present work,the perturbation-response scanning method developed by our group was combined with the molecular dynamics(MD)simulation to identify the key residues controlling the functional movement of proteins.In our method,a physical quantity that is directly related to protein specific function was introduced,and then based on the MD simulation trajectories,the perturbation-response scanning method was used to identify the key residues for functional motions,in which the residues that highly correlated with the fluctuation of the function-related quantity were identified as the key residues controlling the specific functional motions of the protein.Two protein systems,i.e.,the heat shock protein 70 and glutamine binding protein,were selected as case studies to validate the effectiveness of our method.Our calculated results are in good agreement with the experimental results.The location of the key residues in the two proteins are similar,indicating the similar mechanisms behind the performance of their biological functions.

Thermal conductivity of multi-walled carbon nanotubes:Molecular dynamics simulations

Heat conduction in single-walled carbon nanotubes （SWCNTs） has been investigated by using various methods, while less work has been focused on multi-walled carbon nanotubes （MWCNTs）. The thermal conductivities of the double-walled carbon nanotubes （DWCNTs） with two different temperature control methods are studied by using molecular dynamics （MD） simulations. One case is that the heat baths （HBs） are imposed only on the outer wall, while the other is that the HBs are imposed on both the two walls. The results show that the ratio of the thermal conductivity of DWCNTs in the first case to that in the second case is inversely proportional to the ratio of the cross-sectional area of the DWCNT to that of its outer wall. In order to interpret the results and explore the heat conduction mechanisms, the inter-wall thermal transport of DWCNTs is simulated. Analyses of the temperature profiles of a DWCNT and its two walls in the two cases and the inter- wall thermal resistance show that in the first case heat is almost transported only along the outer wall, while in the second case a DWCNT behaves like parallel heat transport channels in which heat is transported along each wall independently. This gives a good explanation of our results and presents the heat conduction mechanisms of MWCNTs.

Molecular Dynamics Simulation of Interaction of Short Lysine Brush and Oppositely Charged Semax Peptides

The possibility of complex formation by short lysine brush and therapeutic Semax peptides was investigated using molecular dynamics method. Lysine dendrimers and polymer brushes are used for drug and other (e.g., DNA, peptides, and polysaccharides) molecules delivery to different target cells. It is known that they could penetrate blood brain barrier. Since short lysine brush is nontoxic, a system containing of such brush and 8 oppositely charged Semax peptides was studied. It was obtained that stable complexes consisting of brush and peptides formed and structures of these complexes were investigated. Such complex can be used in future for delivery of Semax peptides to brain since these peptides have significant antioxidant, antihypoxic and neuroprotective effects.

Molecular dynamics simulations of LiCl association and NaCl association in water by means of ABEEM/MM

Constrained molecular dynamics simulations have been used to investigate the LiCl and NaCl ionic association in water in terms of atom-bond electronegativity equalization method fused into molecular mechanics (ABEEM/MM). The simulations make use of the seven-site fluctuating charge and flexible ABEEM-7P water model, based on which an ion-water interaction potential has been constructed. The mean force and the potential of mean force for LiCl and NaCl in water, the charge distributions, as well as the structural and dynamical properties of contact ion pair dissociation have been investigated. The results are reasonable and informative. For LiCl ion pair in water, the solvent-separated ion pair configurations are more stable than contact ion pair configurations. The calculated PMF for NaCl in water indicates that contact ion pair and solvent-separated ion pair configurations are of comparable stability.

Inhibition of acetylcholinesterase by two genistein derivatives:kinetic analysis,molecular docking and molecular dynamics simulation

In this study two genistein derivatives(G1 and G2)are reported as inhibitors of acetylcholinesterase(AChE)and butyrylcholinesterase(BuChE),and differences in the inhibition of AChE are described.Although they differ in structure by a single methyl group,the inhibitory effect of G1(IC50¼264 nmol/L)on AChE was 80 times stronger than that of G2(IC50¼21,210 nmol/L).Enzyme-kinetic analysis,molecular docking and molecular dynamics(MD)simulations were conducted to better understand the molecular basis for this difference.The results obtained by kinetic analysis demonstrated that G1 can interact with both the catalytic active site and peripheral anionic site of AChE.The predicted binding free energies of two complexes calculated by the molecular mechanics/generalized born surface area(MM/GBSA)method were consistent with the experimental data.The analysis of the individual energy terms suggested that a difference between the net electrostatic contributions(ΔEele+ΔGGB)was responsible for the binding affinities of these two inhibitors.Additionally,analysis of the molecular mechanics and MM/GBSA free energy decomposition revealed that the difference between G1 and G2 originated from interactions with Tyr124,Glu292,Val294 and Phe338 of AChE.In conclusion,the results reveal significant differences at the molecular level in the mechanism of inhibition of AChE by these structurally related compounds.

Surface Effect on Vibration of Timoshenko Nanobeam Based on Generalized Differential Quadrature Method and Molecular Dynamics Simulation

Nanobeams have promising applications in areas such as sensors,actuators,and resonators in nanoelectromechanical systems(NEMS).Considering the effects of gyration inertia,surface layer mass,surface residual stress,and surface Young's modulus,this study develops the vibration equations of the Timoshenko nanobeam.The generalized differential quadrature(GDQ)method and molecular dynamics(MD)simulation are used to study the surface effect on vibration.For a rectangular cross section,surface residual stress and surface Young's modulus are all affected by the height of the cross section rather than by the length-height ratio.If surface layer mass is considered,then the first three natural frequencies all decrease relative to their counterparts in the case in which surface layer mass is ignored.Results show that the effect of gyration inertia on resonance frequency is negligible.Longitudinal vibration does not easily occur relative to the bending and rotation vibrations of nanobeams.In addition,the results obtained by the GDQ method fit those obtained by MD simulation for beams with length-height ratios of 4-8.This study provides insights into the mechanism of the vibration of short and deep nanobeams and sheds light on the quantitative design of the elements in NEMSs.

COMPUTERIZED SIMULATION OF MOLTEN SALT SOLUTION OF Li,KF,Cl SYSTEM BY MOLECULAR DYNAMIC METHOD

The structure and properties of molten salt solution o J Li,K|F,Cl system have been investiged by computerized simulation of molecular dynamic method.The partial RDF,the partial molar energy of mixing and the diffusion coeffients of Li^+,K^+,F^- and Cl^- have been calculated. The results are in agreement with the experimental values.The regularities of the distribution of ions and mieroscopic holes are discussed based on the results of computerized simulation.

Insight into herbicide resistance of W574L mutant Arabidopsis thaliana acetohydroxyacid synthase:molecular dynamics simulations and binding free energy calculations

Acetohydroxyacid synthase(AHAS) is the target enzyme of several classes of herbicides,such as sulfonylureas and imidazolinones.Now many mutant AHASs with herbicide resistance have emerged along with extensive use of herbicides,therefore it is imperative to understand the detailed interaction mechanism and resistance mechanism so as to develop new potent inhibitors for wild-type or resistant AHAS.With the aid of available crystal structures of the Arabidopsis thaliana(At) AHAS-inhibitor complex,molecular dynamics(MD) simulations were used to investigate the interaction and resistance mechanism directly and dynamically at the atomic level.Nanosecond-level MD simulations were performed on six systems consisting of wild-type or W574L mutant AtAHAS in the complex with three sulfonylurea inhibitors,separately,and binding free energy was calculated for each system using the MM-GBSA method.Comprehensive analyses from structural and energetic aspects confirmed the importance of residue W574,and also indicated that W574L mutation might alert the structural charactersistic of the substrate access channel and decrease the binding affinity of inhibitors,which cooperatively weaken the effective channel-blocked effect and finally result in weaker inhibitory effect of inhibitor and corresponding herbicide resistance of W574L mutant.To our knowledge,it is the first report about MD simulations study on the AHAS-related system,which will pave the way to study the interactions between herbicides and wild-type or mutant AHAS dynamically,and decipher the resistance mechanism at the atomic level for better designing new potent anti-resistance herbicides.

Molecular dynamics simulation of single crystal Nickel nanometric machining

Molecular dynamics simulation is carried out to study the nanometric machining of single crystal Nickel(Ni). Through an investigation of atomic displacement and the variation of cutting force, it is found that the latter is in accordance with the number variation of elastic displaced atoms in the workpiece. It is further found that the generation of complex stacking faults is the predominant cause of cutting force fluctuation, and the stacking faults with complex structures lead to work-hardening. The temperature of the cutting tool and workpiece is studied during the machining process. It is concluded that the selection of averaging steps has a significant influence on the system temperature distribution. Thus, the time-spatial averaging method, which has a high accuracy and consistency in temperature distribution, is proposed.

Simulation of He Behavior in Metals With Embedded Atom Method

The embedded-atom method(EAM)is used to study the behavior of helium in meta-ls.By fitting the measured parameters such as the activation energy and the heat of solution,the EAM potentials of helium in nickel are extracted.Based upon the EAM potentials,thebinding energy and the self-trapping of helium in nickel are investigated with molecular dynam-ics simulation.

QM/MM方法的研究

从理论上探讨了QM/MM方法在模拟计算生物大分子体系的运用,实践表明这种方法能提高计算结果的精确性,能有效地降低计算成本.

MD simulation of a copper rod under thermal shock

In this paper, thermoelastic problem of onedimensional copper rod under thermal shock is simulated using molecular dynamics method by adopting embedded atom method potential. The rod is on axis x, the left outermost surface of which is traction free and the right outermost surface is fixed. Free boundary condition is imposed on the outermost surfaces in direction y and z. The left and right ends of the rod are subjected to hot and cold baths, respectively. Temperature, displacement and stress distributions are obtained along the rod at different moments, which are shown to be limited in the mobile region, indicating that the heat propagation speed is limited rather than infinite. This is consistent with the prediction given by generalized thermoelastic theory. From simulation results we find that the speed of heat conduction is the same as the speed of thermal stress wave. In the present paper, the simulations are conducted using the large-scale atomic/molecular massively parallel simulator and completed visualization software.

烟酰胺酶催化水解脱氨反应的QM/MM分子动力学模拟

采用QM(PM3)/MM分子动力学(MD)方法模拟了烟酰胺酶催化烟酰胺水解脱氨形成烟碱酸的反应过程.计算结果表明,硫的亲核进攻是整个反应的速率控制步骤.当改变Ala155所在Loop区的位置,在亲核进攻时,底物能够自由旋转,可以加速亲核进攻过程并降低整个催化反应的能垒.讨论了氨分子的离去过程和质子传递过程的相关细节.为烟酰胺酶的定点突变以及脱氨酶的设计提供了有益的参考.

Atomistic simulation of free transverse vibration of graphene,hexagonal SiC, and BN nanosheets

Free transverse vibration of monolayer graphene, boron nitride (BN), and silicon carbide (SiC) sheets is investigated by using molecular dynamics finite element method. Eigenfrequencies and eigenmodes of these three sheets in rectangular shape are studied with different aspect ratios with respect to various boundary conditions. It is found that aspect ratios and boundary conditions affect in a similar way on natural frequencies of graphene, BN, and SiC sheets. Natural frequencies in all modes decrease with an increase of the sheet’s size. Graphene exhibits the highest natural frequencies, and SiC sheet possesses the lowest ones. Missing atoms have minor effects on natural frequencies in this study.

响应面法优化老化油破乳脱水工艺条件及油水界面的分子动力学模拟

采用不同相对溶解常数的破乳剂对某油田老化油进行破乳脱水,考察了破乳剂种类和用量、助剂种类和用量、温度等因素对脱水率的影响,利用响应面法优化了工艺条件,并通过分子动力学模拟分析了破乳剂对油水界面的作用机制。在单因素实验的基础上,通过响应面法得到老化油破乳脱水的最优工艺条件为破乳剂C用量130 mg/L、温度75℃、助剂NaOH用量0.3%(w),该条件下老化油脱水率达86.57%。主要工艺参数对脱水率的影响从大到小依次为温度、破乳剂用量、助剂用量。分子动力学模拟结果表明,相对溶解常数最大的破乳剂C与老化油体系的界面生成能最高,在油水界面上的扩散系数最大,对老化油的破乳脱水效果最佳。

微过氧化物酶水溶液的ABEEM/MM动力学模拟

应用原子-键电负性均衡浮动电荷分子力场(ABEEM/MM),对微过氧化物酶水溶液进行了分子动力学模拟.研究了水溶液对微过氧化物酶的结构,血红素的皱裂构象以及轴配体咪唑基的取向的影响.结果表明,在水溶液中微过氧化物酶的骨架氨基酸是稳定的,而血红素的皱裂构象在水分子的作用下趋于平面.与血红素轴配体咪唑基键连的组氨酸决定着咪唑基的空间取向,而咪唑基与血红素侧链的丙酸基的静电作用对其取向仅起次要作用.

血红素近轴侧基氢键的ABEEM/MM分子动力学模拟

应用ABEEM/MM浮动电荷力场对鲸鱼肌红蛋白及突变体进行了分子动力学模拟.结果表明,血红素近轴侧基不存在稳定的双氢键,该氢键对轴配体咪唑的取向不起决定性作用,而咪唑的取向与键联的组氨酸有密切联系.同时表明,血红素轴配体的柔性与其邻近的氨基酸和咪唑体积有关.

ABEEMσπ/MM模型对蛋白质G_A88/G_B88水溶液动力学性质的研究

应用ABEEMσπ/MM(σπ水平的原子与键电负性均衡方法融合进分子力学)浮动电荷模型以及显性ABEEM-7P水模型,对GA88和GB88两个蛋白质分子进行了分子动力学模拟.分析了2个蛋白质的动力学性质,包括蛋白质的回旋半径、疏水表面积和亲水表面积、各类原子位置的均方根偏差以及氢键分布.通过对比水溶液和真空下2个蛋白质的回旋半径,表明该模型很好地体现了蛋白质的"电致紧缩"现象;对疏水表面积和亲水表面积的计算表明,GB88中残基与溶剂的相互作用更强一些;非氢原子位置的均方根偏差及氢键分布情况与实验结构相比较表明,ABEEMσπ/MM浮动电荷模型模拟的GA88和GB88的结构与实验结构有很好的一致性,进而说明该模型的合理性和参数的可转移性.

Molecular Simulations in Macromolecular Science

Molecular simulations are now an essential part of modern chemistry and physics,especially for the investigation of macromolecules.They have evolved into mature approaches that can be used effectively to understand the structure-to-property relationships of diverse macromolecular systems.In this article,we provide a tutorial on molecular simulations,focusing on the technical and practical aspects.Several prominent and classical simulation methods and software are introduced.The applications of molecular simulations in various directions of macromolecular science are thenfeatured by representative systems,including self-assembly,crystallization,chemical reaction,and some typical non-equilibrium systems.This tutorial paper provides a useful overview of molecular simulations in the rapid progress of macromolecular science,and suggests guidance for researchers who start exploiting molecular simulations in their study.