Assessment of the elastic properties of amorphous calcium silicates hydrates (I) and (II) structures by molecular dynamics simulation

Based on Hamid model of 11Å tobermorite, amorphous calcium silicates hydrates (or C-S-H) structures (Ca₄Si₆O₁₄(OH)₄?2H₂O as the C-S-H(I) and (CaO)_1.67(SiO₂)(H₂O)_1.75 as the C-S-H(II)) with the Ca/Si ratio of 0.67 and 1.7 are concerned. Then, as the representative ‘globule’ C-S-H, two amorphous C-S-H structures with the size of 5.352 × 4.434 × 4.556 nm³ during the stretch process are simulated at a certain strain rate of 10^?3 ps^?1 by LAMMPS program for molecular dynamics simulation, using ClayFF force field. The tensile stress–strain curves are obtained and analysed. Besides, elastic modulus of the ‘globule’ C-S-H is calculated to assess the elastic modulus of C-S-H phases (the low-density C-S-H – LD C-S-H – and the high-density C-S-H – HD C-S-H), where the porosity is a critical factor for explaining the relationship between ‘globule’ C-S-H at nanoscale and C-S-H phases at microscale. Results show that: (1) The C-S-H(I) structure has transformed from crystalline to amorphous during the annealing process, Young’s moduli in x, y and z directions are almost the same. Besides, the extent of aggregation and aggregation path for water molecules in the structure is different in three directions. (2) Young’s modulus of both amorphous C-S-H(I) and C-S-H(II) structures with a size of about 5 nm under strain rate of 10^?3 ps^?1 at 300 K in three directions is averaged to be equal, of which C-S-H(II) structure is about 60.95 GPa thus can be seen as the elastic modulus of the ‘globule’ C-S-H. (3) Based on the ‘globule’ C-S-H, the LD C-S-H and HD C-S-H can be assessed by using the Self-Consistent Scheme (separately 18.11 and 31.45 GPa) and using the Mori–Tanaka scheme (29.78 and 37.71 GPa), which are close to the nanoindentation experiments by Constantinides et al. (21.7 and 29.4 GPa).     

Interfacial water on crystalline silica: a comparative molecular dynamics simulation study

Understanding the properties of interfacial water at solid–liquid interfaces is important in a wide range of applications. Molecular dynamics is becoming a widespread tool for this purpose. Unfortunately, however, the results of such studies are known to strongly depend on the selection of force fields. It is, therefore, of interest to assess the extent by which the implemented force fields can affect the predicted properties of interfacial water. Two silica surfaces, with low and high surface hydroxyl density, respectively, were simulated implementing four force fields. These force fields yield different orientation and flexibility of surface hydrogen atoms, and also different interaction potentials with water molecules. The properties for interfacial water were quantified by calculating contact angles, atomic density profiles, surface density distributions, hydrogen bond density profiles and residence times for water near the solid substrates. We found that at low surface density of hydroxyl groups, the force field strongly affects the predicted contact angle, while at high density of hydroxyl groups, water wets all surfaces considered. From a molecular-level point of view, our results show that the position and intensity of peaks observed from oxygen and hydrogen atomic density profiles are quite different when different force fields are implemented, even when the simulated contact angles are similar. Particularly, the surfaces simulated by the CLAYFF force field appear to attract water more strongly than those simulated by the Bródka and Zerda force field. It was found that the surface density distributions for water strongly depend on the orientation of surface hydrogen atoms. In all cases, we found an elevated number of hydrogen bonds formed between interfacial water molecules. The hydrogen bond density profile does not depend strongly on the force field implemented to simulate the substrate, suggesting that interfacial water assumes the necessary orientation to maximise the number of water–water hydrogen bonds irrespectively of surface properties. Conversely, the residence time for water molecules near the interface strongly depends on the force field and on the flexibility of surface hydroxyl groups. Specifically, water molecules reside for longer times at contact with rigid substrates with high density of hydroxyl groups. These results should be considered when comparisons between simulated and experimental data are attempted.     

Understanding interaction and dynamics of water molecules in the epoxy via molecular dynamics simulation

The robust structural integrity of the epoxy plays an important role in ensuring the long-term service life of its applications, which is affected by the absorbed moisture. In order to understand the mechanism of the moisture effect, the knowledge of the interaction and dynamics of the water molecules inside the epoxy is of great interest. Molecular dynamics simulation is used in this work to investigate the structure and bonding behaviour of the water molecules in the highly cross-linked epoxy network. When the moisture concentration is low, the water molecules are well dispersed in the cross-linked structure and located in the vicinity of the epoxy functional groups, which predominantly form the hydrogen bond (H-bond) with the epoxy network, resulting in the low water mobility in the epoxy. At the high concentration, the water favourably forms the large cluster due to the predominant water–water H-bond interaction, and the water molecules diffuse primarily inside the cluster, which leads to the high water mobility and the accelerated H-bond dynamics. The variation of the bonding behaviour and dynamics of the water molecules reported here could be exploited to understand the material change and predict the long-term performance of the epoxy-based products during the intended service life.     

Molecular dynamics simulation on the decomposition of type SII hydrogen hydrate and the performance of tetrahydrofuran as a stabiliser

Molecular dynamics simulation is used to study the decomposition and stability of SII hydrogen and hydrogen/tetrahydrofuran (THF) hydrates at 150 K, 220 K and 100 bar. The modelling of the microscopic decomposition process of hydrogen hydrate indicates that the decomposition of hydrogen hydrate is led by the diffusive behaviour of H₂ molecules. The hydrogen/THF hydrate presents higher stability, by comparing the distributions of the tetrahedral angle of H₂O molecules, radial distribution functions of H₂O molecules and mean square displacements or diffusion coefficients of H₂O and H₂ molecules in hydrogen hydrate with those in hydrogen/THF hydrate. It is also found that the resistance of the diffusion behaviour of H₂O and H₂ molecules can be enhanced by encaging THF molecules in the (5¹²6⁴) cavities. Additionally, the motion of THF molecules is restricted due to its high interaction energy barrier. Accordingly, THF, as a stabiliser, is helpful in increasing the stability of hydrogen hydrate.     

2D-QSAR study,molecular docking,and molecular dynamics simulation studies of interaction mechanism between inhibitors and transforming growth factor-beta receptor I (ALK5)

Transforming growth factor type 1 receptor (ALK5) is kinase associated with a wide variety of pathological processes, and inhibition of ALK5 is a good strategy to treat many kinds of cancer and fibrotic diseases. Recently, a series of compounds have been synthesized as ALK5 inhibitors. However, the study of their selectivity against other potential targets remains elusive. In this research, a data-set of ALK5 inhibitors were collected and studied based on the combination of 2D-QSAR, molecular docking and molecular dynamics simulation. The quality of QSAR models were assessed statistically by F, R², and R²_ADJ, proved to be credible. The cross-validations for the models (q²_LOO = 0.571 and 0.629, respectively) showed their robustness, while the external validations (r²_test = 0.703 and 0.764, respectively) showed their predictive power. Besides, the predicted binding free energy results calculated by MM/GBSA method were in accordance with the experimental data, and the van der Waals energy term was the factor that had the most significant impact on ligand binding. What is more, several important residues were found to significantly affect the binding affinity. Finally, based on our analyses above, a proposed series of molecules were designed.     

Molecular dynamics simulation of methane hydrate dissociation by depressurisation

Methane (CH₄) hydrate dissociation and the mechanism by depressurisation are investigated by molecular dynamics (MD) simulation. The hydrate decomposition processes are studied by the ‘vacuum removal method’ and the normal method. It is found that the hydrate decomposition is promoted by depressurisation. The quasi-liquid layer is formed in the hydrate surface layer. The driving force of dissociation is found to be controlled by the concentration gradient between the H₂O molecules of the hydrate surface layer and the H₂O molecules of the hydrate inner layer. The clathrates collapse gradually, and the hydrate decomposes layer by layer. Relative to our previous MD simulation results, this study shows that the rate of the hydrate dissociation by depressurisation is slower than that by the thermal stimulation and the inhibitor injection. This study illustrated that MD simulation can play a significant role in investigating the hydrate decomposition mechanisms.     

A simple method for the simulation of steady-state diffusion through membranes: pressure-tuned,boundary-driven molecular dynamics

We present a novel molecular dynamics-based simulation technique for investigating gas transport through membranes. In our simulations, the main control parameters are the partial pressure for the components on the input side of the membrane and the total pressure on the output side. The essential point of our scheme is that this pressure control should be realised by adjusting the particle numbers in the input and output side control cells indirectly. Although this perturbation is applied sufficiently far from the membrane, the bulk-phase properties are well controlled in a simulation cell of common size. Numerical results are given for silicalite-1 membrane with permeating CH₄, CO₂, H₂ and N₂ gases as well as with binary mixtures of CO₂ with the other three components. To describe interactions between particles, we used the simple shifted and cut Lennard–Jones potential with parameters available in the literature. It is expected that the proposed technique can be applied to several other types of membranes and transported fluids in order to support the development of a deeper understanding of separation processes.     

New insights into the molecular mechanism of methanol-induced inactivation of Thermomyces lanuginosus lipase: a molecular dynamics simulation study

Methanol intolerance of lipase is a major limitation in lipase-catalysed methanolysis reactions. In this study, to understand the molecular mechanism of methanol-induced inactivation of lipases, we performed molecular dynamics (MD) simulations of Thermomyces lanuginosus lipase (TLL) in water and methanol and compared the observed structural and dynamic properties. The solvent accessibility analysis showed that in methanol, polar residues tended to be buried away from the solvent while non-polar residues tended to be more solvent-exposed in comparison to those in water. Moreover, we observed that in methanol, the van der Waals packing of the core residues in two hydrophobic regions of TLL became weak. Additionally, the catalytically relevant hydrogen bond between Asp²⁰¹ OD2 and His²⁵⁸ ND1 in the active site was broken when enzyme was solvated in methanol. This may affect the stability of the tetrahedral intermediates in the catalytic cycle of TLL. Furthermore, compared to in water, some enzyme surface residues displayed enhanced movement in methanol with higher Cα root-mean-square atomic positional fluctuation values. One of such methanol-affecting surface residues (Ile²⁴¹) was chosen for mutation, and MD simulation of the I241E mutant in methanol was conducted. The structural analysis of the mutant showed that replacing a non-polar surface residue with an acidic one at position 241 contributed to the stabilisation of enzyme structure in methanol. Ultimately, these results, while providing molecular-level insights into the destabilising effect of methanol on TLL, highlight the importance of surface residue redesign to improve the stability of lipases in methanol environments.     

New potential inhibitors of mTOR: a computational investigation integrating molecular docking,virtual screening and molecular dynamics simulation

The mTOR (mammalian or mechanistic Target Of Rapamycin), a complex metabolic pathway that involves multiple steps and regulators, is a major human metabolic pathway responsible for cell growth control in response to multiple factors and that is dysregulated in various types of cancer. The classical inhibition of the mTOR pathway is performed by rapamycin and its analogs (rapalogs). Considering that rapamycin binds to an allosteric site and performs a crucial role in the inhibition of the mTOR complex without causing the deleterious side effects common to ATP-competitive inhibitors, we employ ligand-based drug design strategies, such as virtual screening methodology, computational determination of ADME/Tox properties of selected molecules, and molecular dynamics in order to select molecules with the potential to become non-ATP-competitive inhibitors of the mTOR enzymatic complex. Our findings suggest five novel potential mTOR inhibitors, with similar or better properties than the classic inhibitor complex, rapamycin.     

One membrane protein,two structures and six environments: a comparative molecular dynamics simulation study of the bacterial outer membrane protein PagP

PagP is a bacterial outer membrane protein consisting of an 8 stranded transmembrane β-barrel and an N-terminal α-helix. It is an enzyme which catalyses transfer of a palmitoyl chain from a phospholipid to lipid A. Molecular dynamics simulations have been used to compare the dynamic behaviour in simulations starting from two different structures (X-ray vs. NMR) and in six different environments (detergent micelles formed by dodecyl phosphocholine and by octyl glucoside, vs. four species of phospholipid bilayer). Analysis of interactions between the protein and its environment reveals the role played by the N-terminal α-helix, which interacts with the lipid headgroups to lock the PagP molecule into the bilayer. The PagP β-barrel adopts a tilted orientation in lipid bilayers, facilitating access of lipid tails into the mouth of the central binding pocket. In simulations starting from the X-ray structure in lipid bilayer, the L1 and L2 loops move towards one another, leading to the formation of a putative active site by residues H33, D76 and S77 coming closer together.     

Interaction mechanism of insulin with ZnO nanoparticles by replica exchange molecular dynamics simulation

The interaction of ZnO nanoparticles with biological molecules such as proteins is one of the most important and challenging problems in molecular biology. Molecular dynamics (MD) simulations are useful technique for understating the mechanism of various interactions of proteins and nanoparticles. In the present work, the interaction mechanism of insulin with ZnO nanoparticles was studied. Simulation methods including MD and replica exchange molecular dynamics (REMD) and their conditions were surveyed. According to the results obtained by REMD simulation, it was found that insulin interacts with ZnO nanoparticle surface via its polar and charged amino acids. Unfolding insulin at ZnO nanoparticle surface, the terminal parts of its chains play the main role. Due to the linkage between chain of insulin and chain of disulfide bonds, opposite directional movements of N terminal part of chain A (toward nanoparticle surface) and N termini of chain B (toward solution) make insulin unfolding. In unfolding of insulin at this condition, its helix structures convert to random coils at terminal parts chains.     

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

Abstract

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     

Bovine pancreatic trypsin inhibitor crystals with different morphologies: a molecular dynamics simulation study

A molecular dynamics simulation study is reported for three polymorphic protein crystals (4PTI, 5PTI and 6PTI) of bovine pancreatic trypsin inhibitor (BPTI). The simulated lattice constants are in good agreement with experimental data, indicating the reliability of force field used. The fluctuation patterns of peptide chains in the three crystals are similar, and the protein structures are fairly well maintained during simulation. We observe that water forms a pronounced hydration layer near the protein surface. The diffusion coefficients of water in the three crystals are smaller than in bulk phase, and thus, the activation energies are higher. The porosity, fluctuation of peptide chains and solvent-accessible surface area as well as the diffusion coefficients of water and counterion in 5PTI are the largest among the three crystals. The diffusion of water and counterion is anisotropic, and the degree of anisotropy increases in the order of 4PTI < 5PTI < 6PTI. Despite a slight difference, the structural and diffusion properties in the three BPTI crystals are generally close. This simulation study reveals that crystal polymorphism does not significantly affect microscopic properties in the BPTI crystals with different morphologies.     

Comparative study of stability and transport of molecules through cyclic peptide nanotube and aquaporin: a molecular dynamics simulation approach

Abstract

The structural stability and transport properties of the cyclic peptide nanotube (CPN) 8?×?[Cys–Gly–Met–Gly]₂ in different phospholipid bilayers such as POPA (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidic acid), POPE (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine), POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine), POPG (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol) and POPS (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoserine) with water have been investigated using molecular dynamics (MD) simulation. The hydrogen bonds and non-bonded interaction energies were calculated to study the stability in different bilayers. One µs MD simulation in POPA lipid membrane reveals the stability of the cyclic peptide nanotube, and the simulations at various temperatures manifest the higher stability of 8?×?[Cys–Gly–Met–Gly]₂. We demonstrated that the presence of sulphur-containing amino acids in CPN enhances the stability through disulphide bonds between the adjacent rings. Further, the water permeation coefficient of the CPN is calculated and compared with human aquaporin-2 (AQP2) channel protein. It is found that the coefficients are highly comparable to the AQP2 channel though the mechanism of water transport is not similar to AQP 2; the flow of water in the CPN is taking place as a two-line 1–2–1–2 file fashion. In addition to that, the transport behavior of Na⁺ and K⁺ ions, single water molecule, urea and anti-cancer drug fluorouracil were investigated using pulling simulation and potential of mean force calculation. The above transport behavior shows that Na⁺ is trapped in CPN for a longer time than other molecules. Also, the interactions of the ions and molecules in Cα and mid-Cα plane were studied to understand the transport behavior of the CPN. Abbreviations AQP2 Aquaporin-2

CPN Cyclic peptide nanotube

MD Molecular dynamics

POPA 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphatidic acid

POPE 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine

POPG 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol

POPS 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoserine

Communicated by Ramaswamy H. Sarma     

Structural stability of myoglobin and glycomyoglobin: a comparative molecular dynamics simulation study

Glycoproteins are formed as the result of enzymatic glycosylation or chemical glycation in the body, and produced in vitro in industrial processes. The covalently attached carbohydrate molecule(s) confer new properties to the protein, including modified stability. In the present study, the structural stability of a glycoprotein form of myoglobin, bearing a glucose unit in the N-terminus, has been compared with its native form by the use of molecular dynamics simulation. Both structures were subjected to temperatures of 300 and 500 K in an aqueous environment for 10 ns. Changes in secondary structures and RMSD were then assessed. An overall higher stability was detected for glycomyoglobin, for which the most stable segments/residues were highlighted and compared with the native form. The simple addition of a covalently bound glucose is suggested to exert its stabilizing effect via increased contacts with surrounding water molecules, as well as a different pattern of interactions with neighbor residues.

Electronic supplementary material

The online version of this article (doi:10.1007/s10867-015-9383-2) contains supplementary material, which is available to authorized users.     

Atomic insight into designed carbamate-based derivatives as acetylcholine esterase (AChE) inhibitors: a computational study by multiple molecular docking and molecular dynamics simulation

Over 100 variants have been designed and studied, using multiple docking methods such as Autodock Vina, ArgusLab, Molegro Virtual Docker, and Hex-Cuda, to study the effect of alteration in the structure of carbamate-based acetylcholyne esterase (AChE) inhibitors. Sixteen selected systems were then subjected to 14 ns molecular dynamics (MD) simulations. Results from all the docking methods are in agreement. Variants that involved biphenyl substituents possess the most negative binding energies in the ?37.64 to ?39.31 kJ mol^?1 range due to their π–π interactions with AChE aromatic residues. The root mean square deviation values showed that all of these components achieved equilibration after 6 ns. Gyration radius (R_g) and solvent accessibility surface area were calculated to further investigate the AChE conformational changes in the presence of these components. MD simulation results suggested that these components might interact with AChE, possibly with no major changes in AChE secondary and tertiary structures.     

Molecular dynamics simulation,binding free energy calculation and molecular docking of human D-amino acid oxidase (DAAO) with its inhibitors

Schizophrenia is a mental illness; most affected people live in developing countries, and neither appropriate treatment nor commercial drugs are currently available. One possibility is to inhibit human-d-amino acid oxidase (h-DAAO). In this study, molecular dynamic simulations of the monomer, dimer and tetramer forms of h-DAAO complexed with the inhibitor 3-hydroxyquinolin-2(1H)-one(2) were performed. Seven residues, Leu51, Gln53, Leu215, Tyr228, Ile230, Arg283 and Gly313, were identified as essential for interacting with the inhibitor. Molecular docking of h-DAAO with pyrrole, quinoline and kojic acid derivatives, representing 69 known or potential h-DAAO inhibitors, was also performed. The results indicated that the activity of the inhibitor can be improved by modifying the compounds to have a substituent group capable of interacting with the side chain of Tyr228. Van der Waals interactions of the inhibitor with the hydrophobic pocket of h-DAAO and electrostatic interactions or H-bonds with Arg283 and Gly313 were important elements in determining the efficiency of the inhibitor. These results provide information on the interaction between h-DAAO and its inhibitors at the molecular level and can aid in the design of novel inhibitors against h-DAAO for new drug development in the treatment of schizophrenia.     

Dissociation of Abeta(16-22) amyloid fibrils probed by molecular dynamics

The mechanisms of deposition and dissociation are implicated in the assembly of amyloid fibrils. To investigate the kinetics of unbinding of Abeta(16-22) monomers from preformed fibrils, we use molecular dynamics (MD) simulations and the structures for Abeta(16-22) amyloid fibrils. Consistent with experimental studies, the dissociation of Abeta(16-22) peptides involves two main stages, locked and docked, after which peptides unbind. The lifetime of the locked state, in which a peptide retains fibril-like structure and interactions, extends up to 0.5 micros under normal physiological conditions. Upon cooperative rupture of all fibril-like hydrogen bonds (HBs) with the fibril, a peptide enters a docked state. This state is populated by disordered random coil conformations and its lifetime ranges from approximately 10 to 200 ns. The docked state is stabilized by hydrophobic side chain interactions, while the contribution from HBs is small. Our simulations also suggest that the peptides located on fibril edges may form stable beta-strand conformations distinct from the fibril "bulk". We propose that such edge peptides can act as fibril caps, which impede fibril elongation. Our results indicate that the interactions between unbinding peptides constitute the molecular basis for cooperativity of peptide dissociation. The kinetics of fibril growth is reconstructed from unbinding assuming the reversibility of deposition/dissociation pathways. The relation of in silica dissociation kinetics to experimental observations is discussed.     

The enzymatic mechanism of carboxypeptidase: A molecular dynamics study

An MD simulation of the system carboxypeptidase A (CPA) with the tetrapeptide Val-Leu-Phe-Phe has been performed in order to learn about the substrate disposition just prior to nucleophilic attack. We have explored the model in which the substrate does not substitute the zinc-coordinated water (the “water” mechanism). The simulations do suggest as feasible that the Zn-OH₂ group performs a nucleophilic attack on the Phe-Phe peptidic bond. We have also investigated the model in which the carbonyl oxygen displaces the zinc-coordinated water. In this case the substrate and Glu-270 orient themselves to allow an anhydride intermediate during the peptidic bond cleavage (the “anhydride” mechanism). Based on the results of the simulations, both “water” and “anhydride” mechanisms are structurally feasible, although the former model seems more probable on chemical grounds. © 1994 John Wiley & Sons, Inc.     

Exploring the mechanism of a regulatory SNP of KLK3 by molecular dynamics simulation

The SNP -158G>A of KLK3 has been validated as a regulatory SNP (rSNP) by molecular biology assays, but the mechanism of how it affects the binding of an androgen receptor (AR) homodimer with DNA is unclear. In the current study, molecular dynamics simulation was adopted to explain its inner cause. Based on a recent review), three types of intermolecular forces were analyzed, and the differences among them were compared between complexes containing -158 A:T and -158 G:C. Extra hydrophobic contacts caused by the methyl group on the mutated thymine were the most crucial factor to the regulatory effect of this rSNP. Further analysis concerning the relative motion of the two recognition helixes of the AR homodimer indicated that the hydrophobic interactions between the recognition helix B and the major groove containing -158 A:T changed that helix’s motion greatly from swaying in a plane at free state to vibrating slightly around an equilibrium position. A relatively full explanation on the occurrence of rSNP -158G>A is presented here.