Results Of MD Simulations Research Articles

An Atomic Level Interactions of Phosphorylated Tau Repeat with Microtubule using Molecular Modeling Approach

Tau is a microtubule-associated protein abundantly expressed in brain and neuronal cells. Microtubules (MT) are madeup of αβ tubulin heterodimeric subunits. Seven α-tubulin and nine β-tubulin isotypes are reported in humans till date, of which βIII tubulin isotypes are predominantly expressed in the neuronal cells and brain. The C-terminal repeat regions composed of R1, R2, R3 and R4 binds to stabilizes the axonal MT. In several neurodegenerative diseases, tau detaches from MT to form insoluble aggregates leading to tauopathy. Phosphorylation of tau is important for the regulating its structure and function. However, hyperphosphorylation of tau is causes its detachment from the MT. The molecular mechanism which triggers detachment of hyperphosphorylated tau from the MT remains elusive. Therefore, we studied interactions of phosphorylated tau repeat region R2 (TauR2) with neuronal specific βIII tubulin isotypes. Our MD simulation results show a single and double phosphorylation in the TauR2 does not affect the MT binding. However, hyperphosphorylation of TauR2 causes its detachment from the MT. The negatively charged C-terminal tail of the βIII tubulin repels negatively charged phosphorylated TauR2, hence causes the detachment. Also, phosphorylated TauR2 shows poor binding affinity towards neuronal specific MT composed of βIII tubulin isotypes. Our strategy can be potentially used to understand detachment of tau from the MTs composed of different β-tubulin isotypes expressed in specific neurodegenerative disorders. We hope that knowledge of precise molecular interactions between phosphorylated tau repeat and neuronal specific MT will pave the way for developing effective treatments against tau related disorders.

Size and shape dependent thermal properties of rutile TiO2 nanoparticles: a molecular dynamics simulation study

ABSTRACTMolecular dynamics (MD) simulations, based on a recently developed charge optimised many-body interatomic potential (COMB3) for titanium dioxide materials, have been employed to investigate the effects of size and shape on the thermal properties of rutile TiO2 nanoparticles (2–6 nm). The size and shape dependence of the melting temperature, cohesive energy, heat capacity and thermal expansion coefficients have been studied. Our MD simulation results show that the melting point of spherical nanoparticles increases with size increase. On the other hand, the heat capacity and thermal expansion coefficients decrease with increasing nanoparticle size. Also, to predict the thermal properties of rutile TiO2 nanoparticles, we merged two theoretical models (Qi-model and Zhu’s model) proposed for size and shape-dependent thermal properties of nanoparticles. The comparison between our MD simulation results with those predicted by theoretical models showed that the trends observed in our MD simulation results were in good agreement with those suggested by the theoretical models. However, the thermal properties obtained from MD simulations deviated from those calculated theoretically for small nanoparticles which could be due to the edge and corner effects disregarded in the theoretical model.

Interaction of KMP-11 and its mutants with ionic liquid choline dihydrogen phosphate: Multispectroscopic studies aided by docking and molecular dynamics simulations

Binding interactions of KMP-11 with the IL choline dihydrogen phosphate (CDHP) solvent have been explored from multispectroscopic studies in conjunction with docking and molecular dynamics simulations. The protein KMP-11, a vaccine candidate against ‘Leishmaniasis’, does not contain any tryptophan (Trp) in its WT sequence. For this study, two single site Trp mutant proteins Y5W and Y89W of KMP -11 have been generated as Trp used as biomarker by the aid of intrinsic fluorescence. In the former mutant (Y5W) Trp is inserted in the vicinity of the N-terminal, while in the later (Y89W), the same residue is disposed near the C-terminal of the protein. The binding interactions of CDHP with both the mutant proteins have been explored from UV–Vis, steady state and time resolved fluorescence spectroscopic studies. The bimolecular quenching rate constant (kq) at various temperatures, as obtained from fluorescence spectroscopic studies suggest definite but weak binding interactions between the mutant proteins and CDHP IL solvent. This result is further corroborated from the near and far - UV Circular Dichroism (CD) spectra. The possible binding sites of CDHP in the vicinity of WT and mutant proteins and the corresponding binding forces have been predicted from the molecular docking studies. The results of MD simulation further portend minimal or no unfolding in the secondary structures of the WT and the mutant proteins upon addition of CDHP molecule. We believe that this in-depth study featuring the interaction of KMP-11 with IL CDHP will enlighten the fundamental understanding towards the development of improved protein based vaccines in general and KMP-11 guided vaccines in particular for the prevention of VL.

Micro hydration structure of aqueous Li+ by DFT and CPMD

Systematic study on microscopic hydration structure of lithium ion hydrated clusters, [Li(H2O)n]+ (n = 1–20), was carried out by density functional theory (DFT) calculations at ωB97XD/6-311++G(d,p) basis l evel and Car-Parrinello molecular dynamics. The DFT calculation results reveal that the four-coordinated structure is the favorable first hydration sphere for [Li(H2O)n]+ (n = 1–20) clusters in the aqueous phase. The second hydration layer of Li+ is 8 water molecules when n ≥ 12. The energy parameters calculation shows that the structures of the first and second hydration shells are relatively steady. For n > 9, the competitive effects of the second and third hydration layers on water molecules arise and the solvent-solvent interactions for outer hydration shell are strengthened. The results of bond parameters declare that the structure of inner hydration shell has little influence on the H2O molecules of outer hydration layer when the first and second hydration spheres of Li+ are saturated. MD simulation results prove Li+ has a strong first hydration shell with Li–O (I, W) distance of 1.970 A. Around 8.66 water with Li–O (I, W) distance of 4.10 A from the second hydration shell. Both DFT and CPMD show Li+ possesses a second hydration shell which is dominantly surrounded by 8 water molecules.

Enthalpically-driven ligand recognition and cavity solvation of bovine odorant binding protein

Lipocalins are a widely distributed family of extracellular proteins typically involved in the transport of small hydrophobic molecules. To gain new insights into the molecular basis that governs ligand recognition by this ancient protein family, the binding properties of the domain-swapped dimer bovine odorant binding protein (bOBP) and its monomeric mutant bOBP121G+ were characterized using calorimetric techniques and molecular dynamics simulations. Thermal unfolding profiles revealed that the isolated bOBP subunits behave as a cooperative folding unit. In addition, bOBP and bOBP121G+ exhibited similar ligand binding properties, characterized by a non-classical hydrophobic effect signature. The energetic differences in the binding of bOBP to 1-hexen-3-ol and the physiological ligand 1-octen-3-ol were strikingly larger than those observed for the interaction of other lipocalins with congeneric ligands. MD simulations revealed that the recurrent opening of transient pores in the submicrosecond timescale allows a profuse exchange of water molecules between the protein interior and the surrounding solvent. This picture contrasts with other lipocalins whose ligand-free binding cavities are devoid of solvent molecules. Furthermore, the simulations indicated that internal water molecules solvate the protein cavity suboptimally, forming fewer hydrogen bonds and having lower density and higher potential energy than bulk water molecules. Upon ligand occupation, water molecules were displaced from the binding cavity in an amount that depended on the ligand size. Taken together, calorimetric and MD-simulation results are consistent with a significant contribution of cavity desolvation to the enthalpically-driven interaction of bOBP with its hydrophobic ligands.

From in vitro to in silico: Modeling and recombinant production of DT-Diaphorase enzyme

DT-Diaphorase (DTD) belonging to the oxidoreductase family, is among the most important enzymes and is of great significance in present-day biotechnology. Also, it has potential applications in glucose and pyruvate biosensors. Another important role of the DTD enzyme is in the detection of Phenylketonuria disease. According to the above demands, at first, we tried to study molecular cloning and production of recombinant DTD in E. coli BL21 strain. We have successfully cloned, expressed, and purified functionally active diaphorase. The amount of enzyme was increased in 10-h using IPTG induction, and the recombinant protein was purified by Ni–NTA agarose affinity chromatography. After that, the kinetic and thermodynamic parameters of the enzyme, optimum temperature and pH were also investigated to find more in-depth information. In the end, to represent the connections between the structures and function of this enzyme, the molecular dynamics simulations have been considered at two temperatures in which DTD had maximum and minimum activity (310 and 293 K, respectively). The results of MD simulations indicated that the interaction between NADH with phenylalanine 232 residue at 310 K is more severe than other residues. So, to investigate the interaction details of NADH/PHE 232 the DFT calculations were done.

Displacement damage study in tungsten and iron for fusion neutron irradiation

In the present paper, displacement damage in tungsten and iron are studied using the TALYS-1.8 code and molecular dynamics simulations. The TALYS-1.8 code is used to predict the energy spectra of recoils. The MD simulations of self-recoils of up to 200 keV damage energies are carried out to predict the number of Frenkel pairs in iron and tungsten using the LAMMPS code. Time evolution of vacancies and interstitials are studied and discussed. The results of MD simulations are used to calibrate the constant parameters of the Arc-dpa method. The displacement damage cross section of tungsten and iron are calculated for the neutron irradiation of up to 15 MeV energy with the NRT and Arc-dpa approaches. The dpa (Arc-dpa) value at the first wall location of EU DEMO reaches 1.19 dpa/FPY and 0.93 dpa/FPY in iron and tungsten, respectively. Similarly, dpa values in iron and tungsten are also predicted at different neutron fields using the NRT and Arc-dpa mechanism.

In-silico approach to understand the inhibition of corrosion by some potent triazole derivatives of pyrimidine for steel

Density functional theory (DFT) with B3LYP functional and 6-31G* basis set was performed on ten triazole derivatives of pyrimidine used as corrosion inhibitors for steel in 1.0 M HCl solution which led to the optimization of their structures, generation of electronic and other important Quantum chemical descriptors using spartan’14 Software. The computations were carried out in non-protonated and protonated forms. The obtained results show a good correlation between the chemical structures of the inhibitors and their experimental inhibition efficiencies (%IEs). The ranking of these efficiencies (%IEs) nicely matched with the order of a good number of the generated descriptors but with a varying degree of correlation as the majority of the descriptors indicates that I-4 is the best inhibitor among the data set. Molecular dynamic simulations were further carried out on the studied inhibitors with Fe (110) surface using Material Studio 8.0. The obtained results of MD simulations suggest that the interaction was as a result of the chemical adsorption on the steel surface since the binding energy is > 100 kcal mol−1 for all the inhibitors and the best adsorption energy was found to be − 333.783 kcal mol−1 (I-4). This observation is in good agreement with the DFT results and the experimental findings.

Evaluating the suitability of RNA intervention mechanism exerted by some flavonoid molecules against dengue virus MTase RNA capping site: a molecular docking, molecular dynamics simulation, and binding free energy study

Dengue virus (DENV) is one of the most dangerous mosquito-borne human pathogens known to the mankind. Currently, no vaccines or standard therapy is avaliable to treate DENV infection. This makes the drug development against DENV more significant and challenging. The MTase domain of DENV RNA RdRp NS5 is a promising drug target, because this domain hosts the RNA capping process of DENV RNA to escape from human immune system. In the present study, we have analysed the RNA intervention mechanism exerted by flavoniod molecules against NS5 MTase RNA capping site by using molecular docking, molecular dynamics simulation and the binding free energy calculations. The results from the docking analysis confirmed that the RNA intervention mecanism is exerted by the quercetagetin (QGN) molecule with all necessary intermolecular interactions and high binding affinity. Notably, QGN forms strong hydrogen bonding interactions with Asn18, Leu20 and Ser150 residues and π⋅⋅⋅π stacking interaction with Phe25 residue. The apo and QGN bound NS5 MTase and QGN-NS5 MTase complex were used for MD simulation. The results of MD simulation reveal that the RMSD and RMSF values of QGN-MTase complex have increased on comparing the apo protein due to the effect of ligand binding. The binding free energy calulation includes prediction of total binding free energy of ligand-protein complex and per-residue free energy decomposition. The QGN binding to NS5 MTase affects it’s native motion, this result is found from Principal component analysis.Communicated by Ramaswamy H. Sarma

Nucleation kinetics in supercooled Ni50Ti50: Computer simulation data corroborate the validity of the Classical Nucleation Theory

Understanding the crystal nucleation mechanism and kinetics is essential for predicting and controlling numerous natural and industrial processes. However, it is extremely difficult to experimentally determine certain key parameters, such as the critical nucleus size, the interfacial free energy, and the diffusion coefficient in multicomponent liquids. In this work, we used MD data on nucleation rates and diffusion coefficient to analyze the nucleation kinetics in a Ni50Ti50 alloy in the framework of the Classical Nucleation Theory (CNT). Our analysis validates the CNT as a good descriptor of the crystal nucleation rates in this supercooled alloy, corroborating recent results of MD simulation of supercooled Lennard-Jones and BaS liquids.

Multidimensional virtual-system coupled canonical molecular dynamics to compute free-energy landscapes of peptide multimer assembly.

An enhanced-sampling method termed multidimensional virtual-system coupled canonical molecular dynamics (mD-VcMD) method is developed. In many cases, generalized-ensemble methods realizing enhanced sampling, for example, adaptive umbrella sampling, apply an effective potential, which is derived from temporarily assumed canonical distribution as a function of one or more arbitrarily defined reaction coordinates. However, it is not straightforward to estimate the appropriate canonical distribution, especially for cases applying multiple reaction coordinates. The current method, mD-VcMD, does not rely on the form of the canonical distribution. Therefore, it is practically useful to explore a high-dimensional reaction-coordinate space. In this article, formulation of mD-VcMD and its evaluation with the simple molecular models consisting of three or four alanine peptides are presented. We confirmed that mD-VcMD efficiently searched 2D and 3D reaction-coordinate spaces defined as interpeptide distances. Direct comparisons with results of long-term canonical MD simulations revealed that mD-VcMD produces correct canonical ensembles. © 2019 Wiley Periodicals, Inc.

Nuclear magnetic resonance and theoretical simulation study on Cs ion co-adsorbed with other alkali cations on illite

Abstract Illite is known to show highly selective Cs adsorption and can control the migration of Cs in a natural environment. However, the local environment and dynamic behavior of Cs with other ions on illite are not well known. To investigate this system, both NMR and theoretical calculation were used for the study of Cs with other alkali cations on the surface of illite. The order of selectivity for Cs adsorption on illite against other alkali cations is generally Li > Na > K > Rb. The fraction of Cs assigned to inner-sphere complexes as estimated by NMR is in the order of Na > K > Rb > Li, which is different from the order of Cs selectivity, and the difference becomes greater with decreasing Cs molar fraction in solution. This order of inner-sphere complex fraction of Cs is in good agreement with that found by theoretical calculation. The result of MD simulation shows the highest molarity peak for all competing alkali cations at 2–4 A regardless of their fractions and species, but with different distribution and distance from the illite surface. Our results demonstrate that the Cs complexes on the surface of illite are highly dependent on the other hydrated competing alkali cations.

Biomimetic robust superhydrophobic stainless-steel surfaces with antimicrobial activity and molecular dynamics simulation

Wettability is an effective strategy to reduce the adhesion force between bacteria and a solid surface, also is favor to effectively overcome the limitation of the substrate materials and expand their practical applications. Herein, inspired by the special micro/nano structures of the creatures and the bioadhesion of marine mussels, a green and simple two-step method, the laser interference patterning and in-situ polymerization, was used to fabricate the superhydrophobic surface with antibacterial property on the stainless-steel (SS) substrate. As well, this patterned surface also has successfully realized the wettability transition from superhydrophilic to superhydrophobic. Meanwhile, the results of MD simulations directly suggested the PDA@ODA compounds how to adsorb on the SS substrate and interact with water molecules, which was consistent with the experimental. In addition, according to the agar plate assays and fluorescent microscope tests, the obtained specimens presented a certain antimicrobial activity. Moreover, the samples had good robustness in the heat resistance, physical performance and durability, which will expand the application fields and working life.

MD and DSC study of bioactive structural stability of insulin in various imidazolium ionic liquids

Ionic liquids (ILs) have been used as a kind of green solvents trying to preserve protein drugs for many years. However, the protective mechanism of ILs on protein drugs is still unclear, which limits their application. For this reason, a molecular dynamic simulation (MD) was used to investigate the structural stability of insulin in 17 ILs solvents, including 10 pure and 7 hydrated ILs systems. The results of molecular interaction between insulin and ILs indicate insulin is stable in pure ILs with lower hydrogen bond basicity and shorter alkyl chain. And while water content is less than 25.00%, the hydrated ILs also are favorable for protein conservation. Moreover, the micro-DSC experimental results prove that the thermal stability of insulin in hydrated [C2mim][OAC] also support the results of MD simulation. So it can be seen that the ILs with lower hydrogen bond basicity and shorter alkyl chain usually have a protective effect on protein, and the MD simulation provides a new and extraordinary method for screening the protective ILs.

Continuum-scale modeling of helium bubble bursting under plasma-exposed tungsten surfaces

We present a comparison between a continuum-scale drift-diffusion-reaction cluster dynamics prediction of helium retention in low-energy helium plasma exposed tungsten and experimental measurements, in a temperature regime that did not produce tungsten fuzz. Our cluster dynamics model, Xolotl, has been successfully benchmarked to high helium implantation flux MD simulations at relatively low implanted fluence. In this article, we also describe the extension of the Xolotl DDR model to incorporate the effect of bubble bursting, which is observed in very high rate MD simulations, as well as MD simulations at longer times than simulated in our prior benchmarking comparison. The bursting model parameters have been tuned by comparing to MD simulations at a flux of 5.0 × 1027 m−2 s−1, and also compared to lower implanted fluence simulations performed at ~4.0 × 1025 m−2 s−1. This article then reports on the consistency of the Xolotl predictions with respect to the size of the simulated cluster phase space (i.e. the maximum cluster size), initial vacancy concentration, and bubble growth trajectory (maximum number of helium atoms per vacancy). Finally, our simulation results are compared to helium plasma experiments that did not produce fuzz. While the Xolotl predictions including bubble bursting are in quantitative agreement with high-flux MD simulations, the initial comparison to plasma exposure experiments at a flux on the order of 1021 m−2 s−1 disagree by more than an order of magnitude, and in fact cannot reproduce the trends in helium retention with varying exposure temperature. Modifying the initial vacancy concentrations and helium cluster diffusion behavior in Xolotl leads to a reasonable agreement with the experimental observations, although the underlying physical explanation for these modifications remains unclear. The predicted helium content at experimentally relevant fluxes has been shown to be relatively insensitive to the parameters used in the bubble bursting model implemented in Xolotl, although these parameters have a larger influence at higher flux. More systematic comparisons between the modeling predictions with both experiments and MD simulation results is expected to improve the bubble bursting model in Xolotl in the future.

Effect of Ca addition on plastic flow in nanocrystalline magnesium by atomistic simulation

Atomistic simulations are used to study the effect of calcium (Ca) addition on plastic flow of nanocrystalline hexagonal close-packed (hcp) magnesium (Mg) under uniaxial tensile deformation. The nanostructure materials are constructed using the Voronoi tessellation method, and the plastic deformation behavior is studied by molecular dynamics simulation. A second nearest neighbor modified embedded atom method (2NN-MEAM) is applied to represent interatomic potential energy. Calcium atoms with different concentration of 0.0–1.3 wt% are randomly distributed in the magnesium nanocrystal with mean grain size of 8.5 nm as substitution atoms. Surprisingly, deformation twinning is not observed in the samples unlike the easy occurrence of twinning in Mg nanocrystal with coarse-grained structure. Structural analysis demonstrated that plastic deformation occurred in the studied Mg-Ca alloys via slip of partial dislocations, nucleation and growth of disordered atom segments (DAS) inside grains. The continuous accumulation of stacking faults induces hcp to fcc (face centered cubic) phase transformation. MD simulation results show that the tensile stress required for partial dislocation nucleation decreases with increasing Ca concentration. The presence of Ca atoms as solid solution in the structure of nanocrystalline Mg-Ca alloy influences the densities of stacking faults and DAS which promotes nucleation of partial dislocations and DAS.

Experimental and modeling study of isobutane alkylation with C4 olefin catalyzed by Brønsted acidic ionic liquid/sulfuric acid

As a dual solvent-catalyst, sulfonic-acid-functionalized ionic liquids (SFILs) are promising catalysts for the C4 alkylation. In the present work, the effect of the SFILs with different ratios to the H2SO4 on the catalytic performance and interfacial properties for the H2SO4-catalyzed alkylation was investigated by the combination of experiments and MD simulation. Experimental results indicated that compared to pure H2SO4, the introduction of the SFILs can contribute to a higher selectivity of C8-alkylates as well as Research Octane Number (RON), suggesting a higher quality of alkylate. Moreover, the catalytic performance of the SFIL/H2SO4 catalyst is improved with the increased addition ratio of the SFIL into the H2SO4 within the range of 10 wt%. MD simulation results revealed that the obvious density enrichment of the cations of the SFILs at the interface results in a larger interface width, and higher interface number and better dispersion of C4 hydrocarbons at the interface, which can be ascribed to the location of the alkyl chains close to the C4 hydrocarbon phase with the extended and perpendicular behaviors. The improvement of interfacial properties due to the addition of the SFILs is favorable to the enhancement of the quality of alkylate, which is in excellent agreement with experimental results. Hopefully, the useful information in this work can provide a reference to the design of the SFILs and the optimization of the C4 alkylation process.

Molecular dynamics studies of ion beam implantation and patterning of silicon: Effect of noble gas cluster formation

The use of energetic ion beams to induce nanopattern formation at surfaces has been well studied both experimentally and theoretically. However, the influence on morphological evolution of the implanted species themselves remains little understood, particularly in the case when the incident ion species does not interact chemically with the target material. In this work, MD simulation results are presented for cumulative ion bombardment of Si to a fluence of $3\ifmmode\times\else\texttimes\fi{}1{0}^{15}\phantom{\rule{0.28em}{0ex}}\mathrm{c}{\mathrm{m}}^{\ensuremath{-}2}$ or more for a range of incident ion energies (20--1000 eV), angles ($0\ensuremath{-}{85}^{\ensuremath{\circ}}$), and species (Ne, Ar, Kr, Xe). For most cases, the implanted ions are observed to form gas clusters or bubbles beneath the surface as the fluence increases. The implantation and cluster formation decrease in magnitude with increasing ion incidence angle, and remain fairly similar for the heavier-than-Si species (Ar, Kr, and Xe). However, the implantation and cluster formation are much more prominent for Ne irradiation. As the fluence continues to increase beyond $\ensuremath{\sim}1{0}^{15}\phantom{\rule{0.28em}{0ex}}\mathrm{c}{\mathrm{m}}^{\ensuremath{-}2}$, the gas clusters begin to become exposed to the vacuum as the Si layers trapping the gas atoms are eroded by the incident ions. The exposed gas clusters then degas very rapidly, leading to disruption at the surface and to viscous material flow of Si into the void left behind. Comparison to dynamic binary collision approximation (BCA) simulations indicates that cluster formation and degassing contributes to a wide distribution of single-impact emission yields of implanted ions, contrary to intuitive expectations based on BCA simulations. Notably, the increased size and frequency of many-atom implanted ion emission events contributes to a much lower concentration of the implanted species than is otherwise expected from BCA simulations. Additionally, this cluster degassing phenomenon is conjectured to provide a potential ``antipatterning'' mechanism by disrupting or destroying nanopattern ``seeds'' at the surface. This could provide an additional mechanism to improve model predictions of critical angles for patterning transitions, and may also provide at least a partial explanation for the difficulty of obtaining patterns on Ne-bombarded Si surfaces.

Porosity effects on oxygen ions diffusion in the yttria-stabilized zirconia (YSZ) by molecular dynamics simulation

In this paper, the porosity effects on oxygen ions diffusion was investigated in the yttria-stabilized zirconia (YSZ) by molecular dynamics simulation (MD). Different models were simulated to elucidate the role of yttria (Y2O3) concentration (3 to 8 mol% Y2O3), number of pores and pores density and structure (cubic and tetragonal lattice) on the oxygen ions diffusion in YSZ system. MD simulation results showed that the diffusion coefficient of the tetragonal YSZ was smaller than that of the cubic YSZ, the maximum of oxygen ions diffusion coefficient exhibited in the 6 mol% Y2O3 among all the tetragonal YSZ systems. From MD simulation results, it was found that the pores in the YSZ system were retarding the oxygen ions diffusion. For constant porosity, smaller single pore volume resulted in lower D, while higher total porosity also led to smaller D.

Novel coumarin derivatives as potent acetylcholinesterase inhibitors: insight into efficacy, mode and site of inhibition

The inhibitory efficacy of two substituted coumarin derivatives on the activity of neurodegenerative enzyme acetylcholinesterase (AChE) was assessed in aqueous buffer as well as in the presence of human serum albumin (HSA) and compared against standard cholinergic AD drug, Donepezil (DON). The experimental data revealed the inhibition to be of non-competitive type with both the systems showing substantial inhibitory activity on AChE. In fact, one of the tested compounds Chromenyl Coumarate (CC) was found to be better inhibitor (IC50 = 48.49 ± 5.6 nM) than the reference drug DON (IC50 = 74.13 ± 8.3 nM), unequivocally amplifying its importance. The structure of the compound was found to play a vital role in the inhibitory efficiency, validating previous Structure Activity Relationship (SAR) reviews for coumarin. The mechanism of inhibition remained impervious when the experimental medium was switched from aqueous buffer to HSA, albeit noticeable change in the inhibition potency of the compound 3, 3′- Methylene-bis (4-hydroxy coumarin) (MHC) (38%) and CC (35%). Both the coumarin derivatives were observed to bind to the peripheral anionic site (PAS) of AChE and also found to displace the fluorescence marker thioflavinT (ThT) from AChE binding pocket. All experimental observations were seconded by molecular docking and MD simulation results. The inferences drawn in this study form a foundation for further investigation on these compounds; magnifying the probability of their usage as AD drugs and re-emphasizes the significance of drug delivery media while considering the inhibition potencies of targeted drugs.