Molecular Dynamics Investigation Research Articles

Molecular Docking and Molecular Dynamic Investigations of Xanthone-Chalcone Derivatives against Epidermal Growth Factor Receptor for Preliminary Discovery of Novel Anticancer Agent

Epidermal growth factor receptor (EGFR) is found to be overexpressed in cancer cells as it controls angiogenesis, cell signaling, and proliferation mechanisms. Therefore, EGFR has been known as a common target for the initial screening of new anticancer agents. Either xanthone or chalcone has been evaluated as the anticancer agents, and their activity strongly depends on the type and position of the attached functional group. Therefore, molecular hybridization between xanthone and chalcone could yield novel anticancer agents through the EGFR inhibition mechanism. Herein, a series of xanthone-chalcone derivatives with hydrogen-bond-acceptor or hydrogen-bond-donor substituents at ortho, meta, and para positions was evaluated as the EGFR inhibitor. Thirty-seven xanthone-chalcones were designed and docked in the active site of EGFR. Compared to the native ligand, pristine xanthone-chalcone gave a 1.215× stronger binding energy and a 13.97× lower binding constant. Compound 3SH was found to be the most promising candidate due to its strongest binding energy (−9.71 kcal/mol) and the lowest binding constant (0.08 µM). Furthermore, molecular dynamic studies demonstrated that complex EGFR-3SH was stable for 100 ns simulation. These in silico investigations show that the xanthone-chalcone derivative is a promising novel anticancer agent to be examined through in vitro and in vivo assays.

Interfacial structures and dissociation reactions of protic ionic liquids on Li metal surface: A combined first-principles and ab initio molecular dynamics investigation

Interfacial structures and dissociation reactions of protic ionic liquids (PILs) comprising five protic cations with two common sulfonylimide anions on the Li(001) surface were investigated using first-principles calculations and ab initio molecular dynamics simulations. Both the anions rapidly decompose, yielding LiF, Li2O and Li2S species as well as large fragments, e.g. NSO2CF3 and NSO2. Particularly, the proton attached to the N atom generally segregates from the cations and generates LiOH with the O atom from the anions and the surface Li atom. In addition, detailed comparisons of reaction mechanisms between PIL-based and AIL-based systems were also made.

Virtual screening and molecular dynamics investigations using natural compounds against autotaxin for the treatment of chronic pain

Chronic pain is a common and debilitating condition with a huge social and economic burden worldwide. Currently, available drugs in clinics are not adequately effective and possess a variety of severe side effects leading to treatment withdrawal and poor quality of life. Recent findings highlight the potential role of autotaxin (ATX) as a promising novel target for chronic pain management, extending beyond its previously established involvement in arthritis and other neurological disorders, such as Alzheimer’s disease. In the present study, we used a virtual screening strategy by targeting ATX against commercially available natural compounds (enamine- phenotypic screening library) to identify the potential inhibitors for the treatment of chronic pain. After initial identification using molecular docking based virtual screening, molecular mechanics (MM/GBSA), ADMET profiling and molecular dynamics simulation were performed to verify top hits. The computational screening resulted in the identification of fifteen top scoring structurally diverse hits that have free energy of binding (ΔG) values in the range of −25.792 (for compound Enamine_1850) to −74.722 Kcal/mol (for compound Enamine_1687). Moreover, the top-scoring hits have favourable ADME properties as calculated using in-silico algorithms. Additionally, the molecular dynamics simulation revealed the stable nature of protein-ligand interaction and provided information about amino acid residues involved in binding. This study led to the identification of potential autotaxin inhibitors with favourable pharmacokinetic properties. Identified hits may further be investigated for their safety and efficacy potential using in-vitro and in-vivo models of chronic pain. Communicated by Ramaswamy H. Sarma

Cation-π Interactions Greatly Influence Ion Transportability of the Light-Driven Sodium Pump KR2: A Molecular Dynamics Study.

Krokinobacter eikastus rhodopsin 2 (KR2) is a typical light-driven sodium pump. Although wild-type KR2 exhibits high Na+ selectivity, mutagenesis performed on the residues constituting the entrance enables permeation of K+ and Cs+, while the underlying mechanism remains elusive. This study presents a comprehensive molecular dynamics investigation, including force field optimization, metadynamics, and alchemical free energy methods, to explore the N61L/G263F mutant of KR2, which exhibits transportability for K+ and Cs+. The introduced Phe263 residue can directly promote ion binding at the entrance through cation-π interactions, while the N61L mutation can enhance ion binding at Phe46 by relieving steric hindrance. These results suggest that cation-π interactions may significantly influence the ion transportability and selectivity of KR2, which can provide important insights for protein engineering and the design of artificial ion transporters.

Exploring the Role of Globular Domain Locations on an Intrinsically Disordered Region of p53: A Molecular Dynamics Investigation.

The pre-tetramerization loop (PTL) of the human tumor suppressor protein p53 is an intrinsically disordered region (IDR) necessary for the tetramerization process, and its flexibility contributes to the essential conformational changes needed. Although the IDR can be accurately simulated in the traditional manner of molecular dynamics (MD) with the end-to-end distance (EEdist) unhindered, we sought to explore the effects of restraining the EEdist to the values predicted by electron microscopy (EM) and other distances. Simulating the PTL trajectory with a restrained EEdist , we found an increased agreement of nuclear magnetic resonance (NMR) chemical shifts with experiments. Additionally, we observed a plethora of secondary structures and contacts that only appear when the trajectory is restrained. Our findings expand the understanding of the tetramerization of p53 and provide insight into how mutations could make the protein impotent. In particular, our findings demonstrate the importance of restraining the EEdist in studying IDRs and how their conformations change under different conditions. Our results provide a better understanding of the PTL and the conformational dynamics of IDRs in general, which are useful for further studies regarding mutations and their effects on the activity of p53.

Molecular Dynamics Investigation of Shock-Induced Deformation Behavior and Failure Mechanism in Metallic Materials

Molecular Dynamics Investigation of Shock-Induced Deformation Behavior and Failure Mechanism in Metallic Materials

Grand canonical Monte Carlo and molecular dynamics investigation of hydrogen solubility and diffusivity in nonmetallic polyvinyl chloride, polyethylene and polyvinylidene fluoride pipes materials

To choose appropriate nonmetallic pipe materials for reducing hydrogen permeation, the hydrogen permeability in polyvinyl chloride, polyethylene, and polyvinylidene fluoride are studied and compared by molecular dynamics simulations. The findings demonstrate the solubility coefficient of hydrogen in polyvinyl chloride rises as the temperature decreases. However, in polyethylene and polyvinylidene fluoride, the trend is reversed. With the decrease of temperature, the diffusion and permeability coefficients decrease. The diffusion of hydrogen molecules follows the jumping mechanism. Among the materials studied, polyvinylidene fluoride is the most suitable material for hydrogen pipes due to its superior resistance to hydrogen permeation.

A Molecular Dynamics Investigation of Ligand-Mediated PPARγ Transrepression

Background and Hypothesis: PPARγ is a nuclear receptor expressed in most cells of the body and exerts metabolic function, including adipocyte differentiation and insulin sensitization. This mechanism is termed transactivation, where ligand binding leads to transcription of target genes. However, PPARγ also has a transrepression activity, where ligand binding inhibits other transcriptional pathways, leading to regulation of the immune system. While the molecular mechanisms of transactivation are well understood, there is little research on the mechanisms of transrepression. Previous studies have implied that these activity states act independently and can be selected for in small molecule design campaigns, but this has yet to be accomplished. Therefore, the aim of this project was to investigate if distinct molecular interactions exist between PPARγ transactivation versus transrepression using a combined computational and structural biology approach.
 Methods: Molecular dynamics (MD) simulations were performed using the CHARMM molecular modeling software to produce 300 ns simulations of PPARγ-ligand complexes. Simulations were analyzed to identify potential protein-ligand interactions, and distances were measured between atoms of interest and compared.
 Results: Although PPARγ’s binding site is large, structural analyses showed that most ligands remained near their initial starting position within the binding pocket throughout an MD simulation. Starting coordinates were taken from previously solved crystal structures or via manual docking based on molecular similarities. Four residues were identified to consistently interact with most of the ligands: Arg280, Ser342, Glu259, and Cys285. These residues differ from previously reported interactions associated with PPARγ transactivation.
 Conclusion: Our results suggest that these residues may play a role in PPARγ transrepression, but these conclusions are preliminary and should be confirmed through further investigation. Future research would include performing replicate simulations and mutational analyses to further explore the involvement of these residues in PPARγ transrepression. Additional PPARγ ligands should also be explored.

Effects of void defects on the mechanical properties of biphasic calcium phosphate nanoparticles: A molecular dynamics investigation

Porous biphasic calcium phosphate (BCP) ceramics are widely used in bone tissue engineering, and the mechanical properties of BCP implants must be reliable. However, the effects of pore structure (e.g., shape and size) on the mechanical properties are not well understood. In this study, we used molecular dynamics simulations to investigate the influence of pore shape and size on the mechanical behavior of BCP nanoparticles. BCP void models with cylindrical and cuboid pores ranging from 2 to 16 nm in diameter were constructed, and the elastic moduli were calculated. In addition, uniaxial tensile and compressive tests were performed on the models. We found that the pore size had a more significant impact on the mechanical properties of BCP than pore shape. Further, the elastic moduli decreased nonlinearly with increasing pore size. In addition, the tensile and compressive strength also decreased with the increase in pore size, but the ductility improved. Furthermore, deformation and fracture were more likely to occur near the pores and at the phase interfaces as a result of high atomic local strain in the calcium-deficient hydroxyapatite area. The results of this work reveal the effects of pore parameters on the mechanical properties of porous BCP at the nanometer level, which may aid the design of improved porous and multiphase CaP-based biomaterials for bone regeneration.

Molecular dynamics investigation on synthesis of a pH- and temperature-sensitive carbon nanotube loaded with doxorubicin

The many exotic properties of carbon nanotubes (CNTs) make them a powerful attraction in the field of drug delivery systems (DDS). In this work, based on quantum chemical calculation and molecular simulation techniques, polyacrylic acid (PAA) and N-isopropyl acrylamide (NIP) are selected and acted simultaneously on the CNT to form a stable system (FCNT). As a potential DDS, FCNT captures the dispersed doxorubicin (DOX) molecules around it and maintains a stable configuration. In these processes, electrostatic and van der Waals forces act synergistically, with van der Waals forces dominating. Compared to NIP, PAA molecules exhibit stronger adhesion and encapsulation efficiency to CNT and stronger adsorption capacity to DOX. This study reveals the mechanism of action among PAA, NIP, CNT, and DOX, providing feasibility verification and prospective guidance for the experimental synthesis of PAA-NIP-CNT-type multifunctional DDS, and also broadening the idea for exploring more efficient DDS suitable for DOX.

Molecular dynamics investigation on the interfacial thermal resistance between annealed pyrolytic graphite and copper.

Modern highly integrated microelectronic products often face the challenge of internal heat dissipation, leading to a significant decrease in their operational efficiency. Annealed Pyrolytic Graphite (APG), due to its superior thermal conductivity, has garnered attention from researchers. The interface thermal resistance between APG and supporting materials like copper significantly affects heat transfer during APG's operation. Existing studies rarely delve into the influence of factors such as the shape of APG material interfaces on thermal resistance from a microscopic perspective. In this paper, utilizing transient thermo-reflectance method and non-equilibrium molecular dynamics simulations, the interface thermal resistance of the APG-Cu structure was investigated under different conditions. The impact of parameters such as copper thickness, interface micro-surface morphology, and APG thickness on the calculated interface thermal resistance was examined. Simulation results revealed that copper thickness had a minor effect on the interface thermal resistance. This is because the phonon participation ratio remains unaffected by changes in the thickness of the copper layer. The interfacial thermal resistance beneath microscopically cylindrical copper surfaces was considerably lower than that of rectangular copper surfaces. This is because beneath the cylindrical surface, the enlarged interface contact area facilitates enhanced thermal transport between the interfaces. The computed results of the radial distribution function in the paper also indirectly validate this viewpoint. The magnitude of interfacial thermal resistance for different APG layers was influenced by the coupling effect of intermolecular forces and the layered stacking structure of APG. The interfacial thermal resistance under the condition of three layers of APG reaches its minimum value, which is 2.2 × 10-9 (K m2 W-1). Furthermore, from the phonon perspective, it is found that the interfacial thermal resistance with different numbers of APG layers is closely related to the localization or delocalization state of phonons. As the number of APG layers increased, the interface thermal resistance showed a trend of initial decrease followed by an increase, this is because the average phonon participation ratio increases and then decreases with the number of APG layers. The average phonon participation ratio reaches its maximum value of 0.45778 under the condition of three layers of APG.

Design of some potent non-toxic Autoimmune disorder inhibitors based on 2D-QSAR, CoMFA, molecular docking, and molecular dynamics investigations

Current clinical research suggests that inhibitors of protein arginine deiminase 4 (PAD4), major histocompatibility complex (MHC) class II HLA-DQ-ALPHA chain, and thyrotropin receptor (or TSH receptor) which are of biological and therapeutic interest, may show potential in treating rheumatoid arthritis, type 1 diabetes, Graves' disease and other autoimmune disorder. In the present study, a comprehensive analysis was conducted on a collection of 32 compounds concerning their anti-rheumatoid arthritis activity as inhibitors of PAD4. This analysis represents the first instance in which these compounds were computationally examined, employing an in-silico approach that considered 2D-3D QSAR modeling, and molecular docking and was further validated through molecular dynamics and ADMET properties assessment. A credible 2D QSAR (Q_LOO^2 ​= ​0.6611 and R^2 ​= ​0.7535) model was constructed and verified using an external validation test set, Y-randomization, variance inflation factor (VIF), mean effect (MF), and William's plot applicability domain (AD). Ligand-based alignment was implemented in the 3D-QSAR examination. The outcomes demonstrated that CoMFA (uvepls) (Q2LOO ​= ​0.5877; R2 ​= ​0.9983) possess remarkable stability and foresight. The internal validation indicated that CoMFA (uvepls) MIFs display superior predictive capability compared to COMFA (ffdsel). Structural criteria determined by the contour maps of the model and molecular docking simulations were strategically employed to computationally develop 10 new, non-toxic autoimmune disease inhibitors with increased efficacy. Docking tests were done on the newly developed compounds to illustrate their binding mechanism and to identify critical interaction residues inside the active region of rheumatoid arthritis (PDB id: 3BLU). In addition, docking results of the selected designed compounds inside the active sites of type 1 diabetes receptor (6DFX), and Graves' disease receptor (4QT5) demonstrated their rheumatoid arthritis (PDB id: 3BLU) selectivity. A molecular dynamics simulation and binding free energy calculations using the MM/GBSA technique confirmed the stability of the proposed compound D4 inside the rheumatoid arthritis (3BLU) receptor active site. In summary, the results of our investigation might give considerable insight into the future design and development of new autoimmune disease inhibitors.

Ab initio molecular dynamics investigation of the Pt(111)-water interface structure in an alkaline environment with high surface OH-coverages.

In this study, we investigate the structure of the Pt(111)-water interface in an alkaline environment with large OH coverages of 1/3, 2/3 and 1 monolayer using a large well-equilibrated system. We observe that the OH coverage influences both the orientational distribution of the water molecules and their density, with more structure associated with higher coverage. At the same time, there is evidence of a highly dynamic hydrogen bond network on the lower coverage systems with substantial exchange of water between the surface and the solvent. In addition to OH and H2O species, which are preferentially located at the top sites, the 1/3 and 2/3 monolayer surfaces also contain O atoms, which are relatively stable and prefer the hollow sites. In contrast, the 1 monolayer surface shows none of these dynamics, and is unlikely to be active. The dynamic coexistence of O, OH and H2O on Pt(111) electrodes in alkaline conditions necessitates the investigation of several possible reaction paths for processess like ORR and water splitting. Finally, the exchange processes observed between the solvent and the interface underscore the need to explicitly include liquid water in simulations of systems similar to Pt(111).

Elucidating the role of diverse mineralisation paradigms on bone biomechanics - a coarse-grained molecular dynamics investigation.

Bone as a hierarchical composite structure plays a myriad of roles in vertebrate skeletons including providing the structural stability of the body. Despite this critical role, the mechanical behaviour at the sub-micron levels of bone's hierarchy remains poorly understood. At this scale, bone is composed of Mineralised Collagen Fibrils (MCF) embedded within an extra-fibrillar matrix that consists of hydroxyapatite minerals and non-collagenous proteins. Recent experimental studies hint at the significance of the extra-fibrillar matrix in providing the bone with the stiffness and ductility needed to serve its structural roles. However, due to limited resolution of experimental tools, it is not clear how the arrangement of minerals, and in particular their relative distribution between the intra- and extra-fibrillar space contribute to bone's remarkable mechanical properties. In this study, a Coarse Grained Molecular Dynamics (CGMD) framework was developed to study the mechanical properties of MCFs embedded within an extra-fibrillar mineral matrix and the precise roles extra- and intra-fibrillar mineralisation on the load-deformation response was investigated. It was found that the presence of extra-fibrillar mineral resulted in the development of substantial residual stress in the system, by limiting MCF shortening that took place during intra-fibrillar mineralisation, resulting in substantial compressive residual stresses in the extra-fibrillar mineral phase. The simulation results also revealed the crucial role of extra-fibrillar mineralisation in determining the elastic response of the Extrafibrillar mineralised MCF (EFM-MCF) system up to the yield point, while the fibrillar collagen affected the post-yield behaviour. When physiological levels of mineralisation were considered, the mechanical response of the EFM-MCF systems was characterised by high ductility and toughness, with micro-cracks being distributed across the extra-fibrillar matrix, and MCFs effectively bridging these cracks leading to an excellent combination of strength and toughness. Together, these results provide novel insight into the deformation mechanisms of an EFM-MCF system and highlight that this universal building block, which forms the basis for lamellar bone, can provide an excellent balance of stiffness, strength and toughness, achieving mechanical properties that are far beyond the capabilities of the individual constituents acting alone.

Molecular dynamics investigation of the effects of thin periodic defective graphene on the interfacial thermal resistance at liquid–solid interfaces

By coating a heat transfer surface with a thin film, we can improve the heat and mass transfer as in the case of micro heat pipes. This study investigates the effects of periodic defective graphene on the density depletion length and the interfacial thermal resistance at the liquid–solid interface through a nonequilibrium molecular dynamics simulation of a water–graphene–Cu system. The results show that the defect concentration of thin graphene plays an essential role in the interfacial thermal resistance. Specifically, it determines the relationship between the density depletion length and the interfacial thermal resistance between water and solid surfaces. In contrast to a pristine graphene coating, a periodic defective graphene coating affects the density depletion length, while the interfacial thermal resistance at the copper–liquid interface decreases clearly with the defect concentration at the strong interaction strength between thin graphene and water.

Molecular dynamics investigation of shale oil occurrence and adsorption in nanopores: Unveiling wettability and influencing factors

Shale oil, an unconventional petroleum resource, has gained significant attention in the industry. Understanding how shale oils exist in nanopores is crucial for unraveling their flow mechanisms and production prediction. The molecular dynamics simulations are conducted to explore oil occurrence and adsorption in various mineral nanopores, and the wettability and influencing factors. This study reveals a non-uniform fluid density distribution within nanopores, decreasing from the solid wall to the center. Distinct differences are observed between adsorbed and free-state oil phases. The effects of temperature, pressure, mineral type, and pore size effects on wettability, adsorption layer thickness, and molecule proportion are studied. Adsorption energy is calculated using physicochemical methods. Findings show temperature and mineral properties primarily influence shale oil wettability, with less impact from pressure. Adsorption capacity and layer thickness are affected by temperature, mineral type, and size. Octane distribution in nanopores is non-uniform, with a 1.5–1.75 nm layer on non-polar mineral walls and 0.67–1.35 nm on polar minerals. A positive correlation exists between shale oil adsorption on mineral nanopores, layer thickness, and adsorption energy. This study enhances our understanding of oil behavior in nanopores of shale oil reservoirs.

Molecular Dynamics Investigations of Human DNA-Topoisomerase I Interacting with Novel Dewar Valence Photo-Adducts: Insights into Inhibitory Activity.

Chronic exposure to ultraviolet (UV) radiation is known to induce the formation of DNA photo-adducts, including cyclobutane pyrimidine dimers (CPDs) and Dewar valence derivatives (DVs). While CPDs usually occur at higher frequency than DVs, recent studies have shown that the latter display superior selectivity and significant stability in interaction with the human DNA/topoisomerase 1 complex (TOP1). With the aim to deeply investigate the mechanism of interaction of DVs with TOP1, we report here four all-atom molecular dynamic simulations spanning one microsecond. These simulations are focused on the stability and conformational changes of two DNA/TOP1-DV complexes in solution, the data being compared with the biomimetic thymine dimer counterparts. Results from root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) analyses unequivocally confirmed increased stability of the DNA/TOP1-DV complexes throughout the simulation duration. Detailed interaction analyses, uncovering the presence of salt bridges, hydrogen bonds, water-mediated interactions, and hydrophobic interactions, as well as pinpointing the non-covalent interactions within the complexes, enabled the identification of specific TOP1 residues involved in the interactions over time and suggested a potential TOP1 inhibition mechanism in action.

Molecular dynamics investigation of argon evaporation on copper surfaces covered with graphene and carbon nanotubes

The recent advancements in nanoscience have led to a significant improvement in surface characteristics, which play a critical role in heat transfer. In this study, the heat transfer of modified copper-based surfaces covered with graphene sheets and carbon nanotubes (CNTs) is investigated using molecular dynamics method, and compared with the heat transfer of a simple copper surface. To modify the surfaces, various numbers of carbon nanotubes with different heights are used. Investigations are conducted on the dynamics of liquid argon clusters, the distribution of argon density, temperature changes, and the phase transition from liquid to the gas. In comparison to the pre-defined reference surface, heat transfer shows an improvement for the copper-based surface coated with graphene platelets. Similarly, simulation results indicate that the increase in both the quantity and height of carbon nanotubes leads to the enhancement of the heat transfer of the surface. Additionally, it is found that, when CNTs are inserted on a surface, a shorter time is required for liquid argon to reach the temperature of solid surface.

Identification of promising small-molecule inhibitors targeting STK17B for cancer therapeutics: molecular docking and molecular dynamics investigations

Cancer is a complex disease characterized by the uncontrolled growth of abnormal cells, leading to the formation of tumours. STK17B, a member of the DAPK family, has been implicated in various cancers and is considered a potential therapeutic target. However, no drug in the market has been approved for the treatment of STK17 B-associated cancer disease. This research aimed to identify direct inhibitors of STK17B using computational techniques. Ligand-based virtual screening and molecular docking were performed, resulting in the selection of three lead compounds (CID_135698391, CID_135453100, CID_136599608) with superior binding affinities compared to the reference compound dovitinib. While molecular docking simulation revealed specific interactions between the lead compounds and key amino acid residues at the binding pocket of STK17B, molecular dynamics simulations demonstrated that CID_135453100 and CID_136599608 exhibit stable conformations and comparable flexibility to dovitinib. However, CID_135698391 did not perform well using this metric as it displayed poor stability. Overall, small-molecule compounds CID_135453100 and CID_136599608 showed promising binding interactions and stability, suggesting their potential as direct inhibitors of STK17B. These findings could contribute to the exploration of novel therapeutic options targeting STK17B in cancer treatment. Communicated by Ramaswamy H. Sarma

Molecular dynamics investigation on structural and interfacial characteristics of aerosol particles containing mixed organic components

Microscopic morphology plays a significant role in the description of aerosol particle evolution, but the knowledge on particles containing mixed organic matters is insufficient. In this study, molecular simulation (MD) method is employed to investigate the morphologies of particles containing two or three of malonic acid (MA), adipic acid (AA) and eicosane (C20). The key point is the effects of organic species and water content on structural and interfacial characteristics of particles. Results show that all dry particles exhibit the approximate core-shell structure with the shell composed of organic with longer hydrocarbon chain. With water content increasing from 100 to 1000, MA + AA + H2O particles present the core-shell structure with decreasing MA in the core, while particles containing C20 successively exhibit the core-shell structure and the ball-cap structure with three layers. These structural differences are caused by the surface propensity of organics, which is positively correlated with both the length of hydrocarbon chain and the water content. At the particle surface, hydrophobic groups of organic molecules direct towards the gas phase. MA (AA) located between water droplet and C20 cluster orient their hydrophobic groups toward C20. Furthermore, ratios of hydrophilic and hydrophobic atoms (K) at the surface of all studied particles increases with increasing water content, and at each water content the order is K(MA + AA) > K(MA + AA + C20) > K(AA + C20) > K(MA + C20). These findings provide microscopic information support for the development of theoretical model for the particle formation and growth.