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.     

Understanding the folding and stability of a designed WW domain protein with replica exchange molecular dynamics simulations

WW domain proteins are usually regarded as simple models for understanding the folding mechanism of β-sheet. CC45 is an artificial protein that is capable of folding into the same structure as WW domain. In this article, the replica exchange molecular dynamics simulations are performed to investigate the folding mechanism of CC45. The analysis of thermal stability shows that β-hairpin 1 is more stable than β-hairpin 2 during the unfolding process. Free energy analysis shows that the unfolding of this protein substantially proceeds through solvating the smaller β-hairpin 2, followed by the unfolding of β-hairpin 1. We further propose the unfolding process of CC45 and the folding mechanism of two β-hairpins. These results are similar to the previous folding studies of formin binding protein 28 (FBP28). Compared with FBP28, it is found that CC45 has more aromatic residues in N-terminal loop, and these residues contact with C-terminal loop to form the outer hydrophobic core, which increases the stability of CC45. Knowledge about the stability and folding behaviour of CC45 may help in understanding the folding mechanisms of the β-sheet and in designing new WW domains.     

Stability of single sheet GNNQQNY aggregates analyzed by replica exchange molecular dynamics: antiparallel versus parallel association

Protein and peptide aggregation into amyloid plaques is associated with a large variety of neurodegenerative diseases. The definition of the molecular bases of these pathologies is hampered by the transient nature of pre-fibrillar small-oligomers that are considered the toxic species. The ability of the peptide GNNQQNY to form amyloid-like structures makes it a good model to investigate the complex processes involved into amyloid fiber formation. By employing full atomistic replica exchange molecular dynamics simulations, we constructed the free energy surface of small assemblies of GNNQQNY to gain novel insights into the fiber formation process. The calculations suggest that the peptide exhibits a remarkable tendency to form both parallel and antiparallel β-sheets. The data show that GNNQQNY preference for parallel or antiparallel β-sheets is governed by a subtle balance of factors including assemblies’ size, sidechain-sidechain interactions and pH. The samplings analysis provides a rationale to the observed trends.     

Collective motions in proteins: a covariance analysis of atomic fluctuations in molecular dynamics and normal mode simulations.

A method is described for identifying collective motions in proteins from molecular dynamics trajectories or normal mode simulations. The method makes use of the covariances of atomic positional fluctuations. It is illustrated by an analysis of the bovine pancreatic trypsin inhibitor. Comparison of the covariance and cross-correlation matrices shows that the relative motions have many similar features in the different simulations. Many regions of the protein, especially regions of secondary structure, move in a correlated manner. Anharmonic effects, which are included in the molecular dynamics simulations but not in the normal analysis, are of some importance in determining the larger scale collective motions, but not the more local fluctuations. Comparisons of molecular dynamics simulations in the present and absence of solvent indicate that the environment is of significance for the long-range motions.     

Incoherent neutron scattering of copper azurin: a comparison with molecular dynamics simulation results

The low-frequency dynamics of copper azurin has been studied at different temperatures for a dry and deuterium hydrated sample by incoherent neutron scattering and the experimental results have been compared with molecular dynamics (MD) simulations carried out in the same temperature range. Experimental Debye-Waller factors are consistent with a dynamical transition at approximately 200 K which appears partially suppressed in the dry sample. Inelastic and quasielastic scattering indicate that hydration water modulates both vibrational and diffusive motions. The low-temperature experimental dynamical structure factor of the hydrated protein shows an excess of inelastic scattering peaking at about 3 meV and whose position is slightly shifted downwards in the dry sample. Such an excess is reminiscent of the “boson peak” observed in glass-like materials. This vibrational peak is quite well reproduced by MD simulations, although at a lower energy. The experimental quasielastic scattering of the two samples at 300 K shows a two-step relaxation behaviour with similar characteristic times, while the corresponding intensities differ only by a scale factor. Also, MD simulations confirm the two-step diffusive trend, but the slow process seems to be characterized by a decay faster than the experimental one. Comparison with incoherent neutron scattering studies carried out on proteins having different structure indicates that globular proteins display common elastic, quasielastic and inelastic features, with an almost similar hydration dependence, irrespective of their secondary and tertiary structure. Received: 12 October 1998 / Revised version: 19 February 1999 / Accepted: 1 March 1999     

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.     

Mechanical properties of armchair silicene nanoribbons with edge cracks: a molecular dynamics study

Silicene has been proven to be a promising material with attractive electronic properties. During the synthesis of silicene, structural defects such as edge crack are likely to be generated and such defects in silicene have impacts on its properties. Herein, molecular dynamics simulations were performed to investigate the mechanical properties of the armchair silicene nanoribbons (ASiNRs) with edge cracks. Our results showed that the mechanical properties of the ASiNRs decrease because of the existence of edge crack. Both the pristine ASiNRs and the ASiNRs with edge cracks show brittle fracture behaviours. The crack length plays an important role in determining the critical strain and fracture strength of the ASiNRs. Moreover, we investigated the effects of strain rate and temperature on the mechanical properties of the ASiNRs with edge cracks. We observed that the increasing strain rate increases the critical strain and fracture strength while decreasing the Young’s modulus. Low-strain rates also changes the expanded directions of cracks in the ASiNRs. We also found that the increasing temperature could significantly decrease the mechanical properties of the ASiNRs with edge cracks.     

A coupling of homology modeling with multiple molecular dynamics simulation for identifying representative conformation of GPCR structures: a case study on human bombesin receptor subtype-3

In this study, a computational pipeline was therefore devised to overcome homology modeling (HM) bottlenecks. The coupling of HM with molecular dynamics (MD) simulation is useful in that it tackles the sampling deficiency of dynamics simulations by providing good-quality initial guesses for the native structure. Indeed, HM also relaxes the severe requirement of force fields to explore the huge conformational space of protein structures. In this study, the interaction between the human bombesin receptor subtype-3 and MK-5046 was investigated integrating HM, molecular docking, and MD simulations. To improve conformational sampling in typical MD simulations of GPCRs, as in other biomolecules, multiple trajectories with different initial conditions can be employed rather than a single long trajectory. Multiple MD simulations of human bombesin receptor subtype-3 with different initial atomic velocities are applied to sample conformations in the vicinity of the structure generated by HM. The backbone atom conformational space distribution of replicates is analyzed employing principal components analysis. As a result, the averages of structural and dynamic properties over the twenty-one trajectories differ significantly from those obtained from individual trajectories.     

Interaction of Piscidin-1 with zwitterionic versus anionic membranes: a comparative molecular dynamics study

Plasma membrane of each micro-organism has a unique set of lipid composition as a consequence of the environmental adaptation or a response to exposure to antimicrobial peptides (AMPs) as antibiotic agents. Understanding the relationship between lipid composition and action of antimicrobial peptides or considering how different lipid bilayers respond to AMPs may help us design more effective peptide drugs in the future. In this contribution, we intend to elucidate how two currently used membrane models, namely palmitoyl-oleoyl-phosphtidylglycerol (POPG) and 1-palmitoyl-oleoyl-glycero-phosphocholine (POPC), respond to antimicrobial peptide Piscidin-1 (Pis-1).The computed density profile of the peptide as it moves from the bulk solvent toward the membrane core suggests that Pis-1 penetrates into the POPG bilayer less than the POPC membrane. Furthermore, we showed that the two model membranes used in this study have different behavior in the presence of Pis-1. Hence, we suggest that membrane composition could be an important factor in determining lytic ability of peptide drugs to kill a unique bacterial species.

An animated interactive 3D complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:37     

On the importance of van der Waals interaction in the groove binding of DNA with ligands: restrained molecular dynamics study

Comparison of interaction energy between an oligonucleotide and a DNA-binding ligand in the minor and major groove modes was made by use of restrained molecular dynamics. Distortion in DNA was found for the major groove mode whereas less significant changes for both ligand and DNA were detected for the minor groove binding after molecular dynamics simulation. The conformation of the ligand obtained from the major groove mode resembles that computed with the ligand soaked in water. The van der Waals contact energy was found to be as significant as electrostatic energy and more important for difference in binding energy between these two binding modes. The importance of van der Waals force in groove binding was supported by computations on the complex formed by the repressor peptide fragment from the bacteriophage 434 and its operator oligonucleotide.     

Novel missense mutations in gidB gene associated with streptomycin resistance in Mycobacterium tuberculosis: insights from molecular dynamics

Streptomycin was the first antibiotic used for the treatment of tuberculosis by inhibiting translational proof reading. Point mutation in gidB gene encoding S-adenosyl methionine (SAM)-dependent 7-methylguanosine (m7G) methyltransferase required for methylation of 16S rRNA confers streptomycin resistance. As there was no structural substantiation experimentally, gidB protein model was built by threading algorithm. In this work, molecular dynamics (MD) simulations coupled with binding free energy calculations were performed to outline the mechanism underlying high-level streptomycin resistance associated with three novel missense mutants including S70R, T146M, and R187M. Results from dynamics analyses suggested that the structure distortion in the binding pocket of gidB mutants modulate SAM binding affinity. At the structural level, these conformational changes bring substantial decrease in the number of residues involved in hydrogen bonding and dramatically reduce thermodynamic stability of mutant gidB–SAM complexes. The outcome of comparative analysis of the MD simulation trajectories revealed lower conformational stability associated with higher flexibility in mutants relative to the wild-type, turns to be major factor driving the emergence of drug resistance toward antibiotic. This study will pave way toward design and development of resistant defiant gidB inhibitors as potent anti-TB agents.     

Effects of cholesterol concentration on the interaction of cytarabine with lipid membranes: a molecular dynamics simulation study

Liposomal cytarabine, DepoCyt, is a chemotherapy agent which is used in cancer treatment. This form of cytarabine has more efficacy and fewer side effects relative to the other forms. Since DepoCyt contains the cytarabine encapsulated within phosphatidylcholine and the sterol molecules, we modeled dioleoylphosphatidylcholine (DOPC)/cholesterol bilayer membrane as a carrier for cytarabine to study drug–bilayer interactions. For this purpose, we performed a series of united-atom molecular dynamics (MD) simulations for 25?ns to investigate the interactions between cytarabine and cholesterol-containing DOPC lipid bilayers. Only the uncharged form of cytarabine molecule was investigated. In this study, different levels of the cholesterol content (0, 20, and 40%) were used. MD simulations allowed us to determine dynamical and structural properties of the bilayer membrane and to estimate the preferred location and orientation of the cytarabine molecule inside the bilayer membrane. Properties such as membrane thickness, area per lipid, diffusion coefficient, mass density, bilayer packing, order parameters, and intermolecular interactions were examined. The results show that by increasing the cholesterol concentration in the lipid bilayers, the bilayer thickness increases and area per lipid decreases. Moreover, in accordance with the experiments, our calculations show that cholesterol molecules have ordering effect on the hydrocarbon acyl chains. Furthermore, the cytarabine molecule preferentially occupies the polar region of the lipid head groups to form specific interactions (hydrogen bonds). Our results fully support the experimental data. Our finding about drug–bilayer interaction is crucial for the liposomal drug design.     

Tick-borne encephalitis virus in northern Italy: molecular analysis, relationships with density and seasonal dynamics of Ixodes ricinus

Ixodes ricinus ticks were collected from dragging vegetation and from shot roe deer in the province of Trento and Belluno in northern Italy. Ticks were pooled for analyses and from 1060 pools of ticks collected in the province of Belluno and 12390 tick samples collected in Trentino, four proved positive by immunofluorescence microscopy using a tick-borne encephalitis (TBE)-specific antiserum. The identity of the virus isolates was determined by RT-PCR cycle sequencing and they were all found to be closely similar (> 98% nucleotide identity) to typical western European TBE complex viruses as found in Austria. The isolates from Trentino differed from the Neudorfl strain of western European TBE virus at eight nucleotide positions but as these nucleotide substitutions were all synonymous, there were no amino acid changes. These results imply that the virus isolates in Trentino have changed slightly from the typical European strains isolated in nearby Austria. The abundance of questing ticks and ticks feeding on roe deer was greater in TBE positive hunting districts than in hunting districts where TBE complex viruses were only probable or believed to be absent. In TBE positive and probable districts synchrony in the seasonal dynamics of larvae and nymphs of L. ricinus was observed. This study provides evidence to suggest that roe deer may have an important role to play in the maintenance of tick density and in the persistence of TBE virus.     

Probing the interactions of the solvated electron with DNA by molecular dynamics simulations: II. bromodeoxyuridine-thymidine mismatched DNA

The interaction of solvated electrons with DNA results in various types of DNA lesions. The in vitro and in vivo sensitisation of DNA to -induced damage is achieved by incorporation of the electron-affinity radiosensitiser bromodeoxyuridine (BUdR) in place of thymidine. However, in DNA duplexes containing single-stranded regions (bulged BUdR-DNA), the type of lesion is different and the efficiency of damage is enhanced. In particular, DNA interstrand crosslinks (ICL) form at high efficiency in bulged DNA but are not detectable in completely duplex DNA. Knowledge about the processes and interactions leading to these differences is obscure. Previously, we addressed the problem by applying molecular modelling and molecular dynamics (MD) simulations to a system of normal (BUdR·A)-DNA and a hydrated electron, where the excess electron was modelled as a localised eˉ(H₂O)₆ anionic cluster. The goal of the present study was to apply the same MD simulation to a wobble system, containing a pyrimidine–pyrimidine mismatched base pair, BUdR·T. The results show an overall dynamic pattern similar to that of the motion around normal DNA. However, the number of configuration states when was particularly close to DNA is different. Moreover, in the (BUdR·T)-wobble DNA system, the electron frequently approaches the brominated strand, including BUdR, which was not observed with the normal (BUdR·A)-DNA. The structure and exchange of water at the sites of immobilisation near DNA were also characterised. The structural dynamics of the wobble DNA is prone to more extensive perturbations, including frequent formation of cross-strand (cs) interatomic contacts. The structural deviations correlated with approaching DNA from the major groove side, with sodium ions trapped deep in the minor groove. Altogether, the obtained results confirm and/or throw light on dynamic-structure determinants possibly responsible for the enhanced radiation damage of wobble DNA. Figure The structure of the tightly bound single water-layer between the DNA and the electron (Site-8, five H₂O molecules, bold capped sticks); the rest of the “second” shell waters (lines, in atom type colour) surround the ˉ(H₂O)₆ cluster (yellow, space fill). Orange dashed lines H-bonds; only one of the five molecules from the single H₂O layer mediates a single-step H-bond bridge with N7(A8); the other four present a network of two(three)-step H-bond bridges between DNA/ partner atoms     

Conformation, dynamics, solvation and relative stabilities of selected beta-hexopyranoses in water: a molecular dynamics study with the GROMOS 45A4 force field

The present article reports long timescale (200 ns) simulations of four beta-D-hexopyranoses (beta-D-glucose, beta-D-mannose, beta-D-galactose and beta-D-talose) using explicit-solvent (water) molecular dynamics and vacuum stochastic dynamics simulations together with the GROMOS 45A4 force field. Free-energy and solvation free-energy differences between the four compounds are also calculated using thermodynamic integration. Along with previous experimental findings, the present results suggest that the formation of intramolecular hydrogen-bonds in water is an 'opportunistic' consequence of the close proximity of hydrogen-bonding groups, rather than a major conformational driving force promoting this proximity. In particular, the conformational preferences of the hydroxymethyl group in aqueous environment appear to be dominated by 1,3-syn-diaxial repulsion, with gauche and solvation effects being secondary, and intramolecular hydrogen-bonding essentially negligible. The rotational dynamics of the exocyclic hydroxyl groups, which cannot be probed experimentally, is found to be rapid (10-100 ps timescale) and correlated (flip-flop hydrogen-bonds interconverting preferentially through an asynchronous disrotatory pathway). Structured solvent environments are observed between the ring and lactol oxygen atoms, as well as between the 4-OH and hydroxymethyl groups. The calculated stability differences between the four compounds are dominated by intramolecular effects, while the corresponding differences in solvation free energies are small. An inversion of the stereochemistry at either C(2) or C(4) from equatorial to axial is associated with a raise in free energy. Finally, the particularly low hydrophilicity of beta-D-talose appears to be caused by the formation of a high-occurrence hydrogen-bonded bridge between the 1,3-syn-diaxial 2-OH and 4-OH groups. Overall, good agreement is found with available experimental and theoretical data on the structural, dynamical, solvation and energetic properties of these compounds. However, this detailed comparison also reveals some discrepancies, suggesting the need (and providing a solid basis) for further refinement.     

Interaction of copper organometallic precursors with barrier layers of Ti, Ta and W and their nitrides: a first-principles molecular dynamics study

Processes for the deposition of copper films on transition metal barrier layers by means CVD using organometallic precursors are often found to lead to poor adhesion characteristics of the grown film. By means of first-principles molecular dynamics simulations, we show that the source of the problem is the strong reactivity of the surfaces toward the precursors, which decompose spontaneously upon contact with the surface leading to contamination of the interface. Our simulations consider Ti, Ta, and W as barrier layers, and Cu(hfac)-(tmvs) as precursor. In contrast, we show that surfaces of these metals properly passivated with nitrogen, in such a way that only N atoms are exposed on the surface, are much less active and do not lead to decomposition of the precursor. We propose this passivation procedure as a practical solution to the adhesion problem. Figure CupraSelect on the WN (100) surface     

Structural insights into the interactions of phorbol ester and bryostatin complexed with protein kinase C: a comparative molecular dynamics simulation study

Protein kinase C (PKC) isozymes are important regulatory enzymes that have been implicated in many diseases, including cancer, Alzheimer’s disease, and in the eradication of HIV/AIDS. Given their potential clinical ramifications, PKC modulators, e.g. phorbol esters and bryostatin, are also of great interest in the drug development. However, structural details on the binding between PKC and its modulators, especially bryostatin – the highly potent and non-tumor promoting activator for PKCs, are still lacking. Here, we report the first comparative molecular dynamics study aimed at gaining structural insight into the mechanisms by which the PKC delta cys2 activator domain is used in its binding to phorbol ester and bryostatin-1. As anticipated in the phorbol ester binding, hydrogen bonds are formed through the backbone atoms of Thr242, Leu251, and Gly253 of PKC. However, the opposition of H-bond formation between Thr242 and Gly253 may cause the phorbol ester complex to become less stable when compared with the bryostatin binding. For the PKC delta-bryostatin complex, hydrogen bonds are formed between the Gly253 backbone carbonyl and the C30 carbomethoxy substituent of the ligand. Additionally, the indole Nε1 of the highly homologous Trp252 also forms an H-bond to the C20 ester group on bryostatin. Backbone fluctuations also suggest that this latter H-bond formation may abrogate the transient interaction between Trp252 and His269, thus dampening the fluctuations observed on the nearby Zn²⁺-coordinating residues. This new dynamic fluctuation dampening model can potentially benefit future design of new PKC modulators.     

Mutants of monomeric red fluorescent protein mRFP1 at residue 66: Structure modeling by molecular dynamics and search for correlations with spectral properties

To study the interrelation between the spectral and structural properties of fluorescent proteins, structures of mutants of monomeric red fluorescent protein mRFP1 with all possible point mutations of Glu66 (except replacement by Pro) were simulated by molecular dynamics. A global search for correlations between geometrical structure parameters and some spectral characteristics (absorption maximum wavelength, integral extinction coefficient at the absorption maximum, excitation maximum wavelength, emission maximum wavelength, and quantum yield) was performed for the chromophore and its 6 A environment in mRFP1, Q66A, Q66L, Q66S, Q66C, Q66H, and Q66N. The correlation coefficients (0.81-0.87) were maximal for torsion angles in phenolic and imidazolidine rings as well as for torsion angles in the regions of connection between these rings and chromophore attachment to beta-barrel. The data can be used to predict the spectral properties of fluorescent proteins based on their structures and to reveal promising positions for directed mutagenesis.