Full-atom Molecular Dynamics Simulations Research Articles

C₆₀-dyad aggregates: self-organized structures in aqueous solutions.

Extensive full-atomistic molecular dynamics simulations are performed to study the self-organization of C60-fullerene dyad molecules in water, namely phenyl-C61-butyric acid methyl ester and fulleropyrrolidines, which have two elements of ordering, the hydrophobic fullerene cage and the hydrophilic/ionic group. While pristine fullerene or phenyl-C61-butyric acid methyl ester forms spherical droplets in order to minimize the surface tension, the amphiphilic nature of charged solute molecules leads to the formation of supramolecular assemblies having cylindrical shape driven by charge repulsion between the ionic groups located on the surface of the aggregates. We show that formation of non-spherical micelles is the geometrical consequence if the fullerene derivatives are considered as surfactants where the ionized groups are only hydrophilic unit. The agglomeration behavior of fullerenes is evaluated by determining sizes of the clusters, solvent accessible surface areas, and shape parameters. By changing the size of the counterions from chloride over iodide to perchlorate we find a thickening of the cylinder-like structures which can be explained by stronger condensation of larger ions and thus partial screening of the charge repulsion on the cluster surface. The reason for the size dependence of counterion condensation is the formation of a stronger hydration shell in case of small ions which in turn are repelled from the fullerene aggregates. Simulations are also in good agreement with the experimentally observed morphologies of decorated C60-nanoparticles.

P17 - Glyoxalase II promotes "in vitro" S-glutathionylation

S-glutathionylation involves the reversible formation of a mix disulphide-bridge between specific cysteine and a molecule of glutathione, the major non-protein antioxidant compound in the cell. Mechanisms of protein S-glutathionylation are far to be completely understood and several reactions can promote it, either spontaneously or catalyzed. For the first time Glo II enzyme was studied as a new potential candidate to promote S-glutathionylation. To demonstrate its active involvement in protein glutathionylation were used actin, malate dehydrogenase and GAPDH purified proteins, which are known to be glutathionylated, for in vitro experiments..This work shows active involvement of cytosolic Glo II for in vitro protein S-glutathionylation. To confirm the role of Glo II, preliminary protein-protein docking studies was performed between Glo II and human actin. The data showed a high propensity to aggregate with other proteins through its catalytic site Further, in silico investigation of Glo II stability and behavior, conducted through full atom molecular dynamics simulations, showed an high folding stability together with a great affinity towards its own reaction product glutathione both protonated (GSH) and unprotonated (GS-). These studies, revealed that GloII, using its natural substrate SLG, allow a rapid and specific protein-SSG formation, leading enzymatic regulation of S-glutathionylation in proteins of different origin and cellular compartmentalization.

On the Improvement of Free-Energy Calculation from Steered Molecular Dynamics Simulations Using Adaptive Stochastic Perturbation Protocols

The potential of mean force (PMF) calculation in single molecule manipulation experiments performed via the steered molecular dynamics (SMD) technique is a computationally very demanding task because the analyzed system has to be perturbed very slowly to be kept close to equilibrium. Faster perturbations, far from equilibrium, increase dissipation and move the average work away from the underlying free energy profile, and thus introduce a bias into the PMF estimate. The Jarzynski equality offers a way to overcome the bias problem by being able to produce an exact estimate of the free energy difference, regardless of the perturbation regime. However, with a limited number of samples and high dissipation the Jarzynski equality also introduces a bias. In our previous work, based on the Brownian motion formalism, we introduced three stochastic perturbation protocols aimed at improving the PMF calculation with the Jarzynski equality in single molecule manipulation experiments and analogous computer simulations. This paper describes the PMF reconstruction results based on full-atom molecular dynamics simulations, obtained with those three protocols. We also want to show that the protocols are applicable with the second-order cumulant expansion formula. Our protocols offer a very noticeable improvement over the simple constant velocity pulling. They are able to produce an acceptable estimate of PMF with a significantly reduced bias, even with very fast perturbation regimes. Therefore, the protocols can be adopted as practical and efficient tools for the analysis of mechanical properties of biological molecules.

The cooperative behaviour of antimicrobial peptides in model membranes

A systematic analysis of the hypothesis of the antimicrobial peptides' (AMPs) cooperative action is performed by means of full atomistic molecular dynamics simulations accompanied by circular dichroism experiments. Several AMPs from the aurein family (2.5,2.6, 3.1), have a similar sequence in the first ten amino acids, are investigated in different environments including aqueous solution, trifluoroethanol (TFE), palmitoyloleoylphosphatidylethanolamine (POPE), and palmitoyloleoylphosphatidylglycerol (POPG) lipid bilayers. It is found that the cooperative effect is stronger in aqueous solution and weaker in TFE. Moreover, in the presence of membranes, the cooperative effect plays an important role in the peptide/lipid bilayer interaction. The action of AMPs is a competition of the hydrophobic interactions between the side chains of the peptides and the hydrophobic region of lipid molecules, as well as the intra peptide interaction. The aureins 2.5-COOH and 2.6-COOH form a hydrophobic aggregate to minimize the interaction between the hydrophobic group and the water. Once that the peptides reach the water/lipid interface the hydrophobic aggregate becomes smaller and the peptides start to penetrate into the membrane. In contrast, aurein 3.1-COOH forms only a transient aggregate which disintegrates once the peptides reached the membrane, and it shows no cooperativity in membrane penetration.

Validation of classical force fields for the description of thermo-mechanical properties of transition metal materials.

It is demonstrated that classical force fields validated through the density functional theory (DFT) calculations of small titanium and nickel clusters can be applied for the description of thermo-mechanical properties of corresponding materials. This has been achieved by means of full-atom molecular dynamics simulations of nanoindentation of amorphous and nanostructured Ti and Ni-Ti materials. The theoretical analysis performed and comparison with experimental data demonstrate that the utilized classical force fields for Ti-Ti, Ni-Ni and Ni-Ti interactions describe reasonably well hardness and the Young's modulus of these materials. This observation is of the general nature and can be utilized for similar numerical exploration of thermo-mechanical properties of a broad range of materials.

Molecular Description of Surfactant-like Peptide Based Membranes

For first time surfactant-like peptide (SLP) based membranes were investigated by full atomistic molecular dynamics simulations. Two different classes of membranes were simulated to quantify the impact of both nonpolar tail and hydrophilic head on the membrane properties. Structural analysis in terms of planar RDFs, density mass profiles, and 2D thickness maps was performed to evaluate the influence of the hydrophobic tail and hydrophilic head in the membrane structural pattern. Unlike what is observed in case of SLP membrane, a lipid membrane has low and short-range local ordering that imposes a significant difference between the two types of membranes. While the lipid membrane interactions are mainly van der Waals for the SLP membrane, both contributions are relevant. This result indirectly implies lower conformational flexibility of SLP and, therefore, their lower potential for live systems. On the basis of the pattern of structuring the membrane in equilibrium, we classified roughly into three different types: (a) those uniform and well ordered, with small variations in thickness and without water inside and therefore no flaw in the hydrogen bond network, (b) those with appreciable variations in structure, with fixed small holes that act as pores for water confinement and defects in the hydrogen bonding network, and (c) a group that has the same properties of the group (a) but present an undulating surface rather than a planar surface.

Insights into the influence of 5-HT2c aminoacidic variants with the inhibitory action of serotonin inverse agonists and antagonists

Specific modulation of serotonin 5-HT(2C) G protein-coupled receptors may be therapeutic for obesity and neuropsychiatric disorders. The different efficacy of drugs targeting these receptors are due to the presence of genetic variants in population and this variability is still hard to predict. Therefore, in order to administer the more suitable drug, taking into account patient genotype, it is necessary to know the molecular effects of its gene nucleotide variations. In this work, starting from an accurate 3D model of 5-HT(2C), we focus on the prediction of the possible effect of some single nucleotide polymorphisms (SNPs) producing amino acidic changes in proximity of the 5-HT(2C) ligand binding site. Particularly we chose a set of 5-HT(2C) inverse agonists and antagonists which have high inhibitory activity. After prediction of the structures of the receptor-ligand complexes using molecular docking tools, we performed full atom molecular dynamics simulations in explicit lipid bilayer monitoring the interactions between ligands and trans-membrane helices of the receptor, trying to infer relations with their biological activity. Serotonin, as the natural ligand was chosen as reference compound to advance a hypothesis able to explain the receptor inhibition mechanism. Indeed we observed a different behavior between the antagonists and inverse agonist with respect to serotonin or unbounded receptor, which could be responsible, even if not directly, of receptor's inactivation. Furthermore, we analyzed five aminoacidic variants of 5HT(2C) receptor observing alterations in the interactions between ligands and receptor which give rise to changes of free energy values for every complex considered.

Tensile deformation and failure of amyloid and amyloid-like protein fibrils

Here we report a series of full atomistic molecular dynamics simulations of six amyloid or amyloid-like protein fibrils in order to systematically understand the effect of different secondary structure motifs on the mechanical tensile and failure response of cross- protein fibrils. We find a similar failure behavior across the six structures; an initial failure event occurs at small strains involving cooperative rupture of a group of hydrogen bonds, followed by a slow one-by-one hydrogen bond rupture process as the remaining -sheets peel off with very low applied stress. We also find that the ultimate tensile strength of the protein fibrils investigated scales directly with the number of hydrogen bonds per unit area which break in the initial rupture event. Our results provide insights into structure–property relationships in protein fibrils important for disease and engineering applications and lay the groundwork for the development of materials selection criteria for the design of de novo amyloid-based functional biomaterials.

Specialized Dynamical Properties of Promiscuous Residues Revealed by Simulated Conformational Ensembles

The ability to interact with different partners is one of the most important features in proteins. Proteins that bind a large number of partners (hubs) have been often associated with intrinsic disorder. However, many examples exist of hubs with an ordered structure, and evidence of a general mechanism promoting promiscuity in ordered proteins is still elusive. An intriguing hypothesis is that promiscuous binding sites have specific dynamical properties, distinct from the rest of the interface and pre-existing in the protein isolated state. Here, we present the first comprehensive study of the intrinsic dynamics of promiscuous residues in a large protein data set. Different computational methods, from coarse-grained elastic models to geometry-based sampling methods and to full-atom Molecular Dynamics simulations, were used to generate conformational ensembles for the isolated proteins. The flexibility and dynamic correlations of interface residues with a different degree of binding promiscuity were calculated and compared considering side chain and backbone motions, the latter both on a local and on a global scale. The study revealed that (a) promiscuous residues tend to be more flexible than nonpromiscuous ones, (b) this additional flexibility has a higher degree of organization, and (c) evolutionary conservation and binding promiscuity have opposite effects on intrinsic dynamics. Findings on simulated ensembles were also validated on ensembles of experimental structures extracted from the Protein Data Bank (PDB). Additionally, the low occurrence of single nucleotide polymorphisms observed for promiscuous residues indicated a tendency to preserve binding diversity at these positions. A case study on two ubiquitin-like proteins exemplifies how binding promiscuity in evolutionary related proteins can be modulated by the fine-tuning of the interface dynamics. The interplay between promiscuity and flexibility highlighted here can inspire new directions in protein–protein interaction prediction and design methods.

Molecular Dynamics Simulation on Compatibility and the Glass Transition Temperature of HTPB/Plasticizer Blends

By means of full atomistic molecular dynamics (MD) simulation, the solubility parameters for hydroxyl-terminated polybutadiene (HTPB), dioctyl sebacate (DOS), dioctyl adipate (DOA), dibutyl phthalate (DBP), dioctyl phthalate (DOP), nitrated esters nitroglycerine (NG) and diethylene glycol dinitrate (DEGDN) are calculated and the results are in agreement with the literature values. Furthermore, in order to reveal the HTPB/plasticizer blend property, the specific volume vs. temperature curves of the blend systems are simulated by employing MD simulation to obtain the glass transition temperature (Tg). From the specific volume vs. temperature curve, the Tg of HTPB, HTPB/DOS, HTPB/DOA, HTPB/DBP, HTPB/DOP, HTPB/NG and HTPB/DEGDN are 197.54, 176.30, 183.11, 189.27,187.40, 200.03 and 205.31 K, respectively. It should be pointed out that as for HTPB and DOS, DOA, DBP, DOP, the solubility parameters are similar and there is only one glass transition of the blend system, these indicate that these studied blend systems are miscible, but HTPB/NG and HTPB/DEGDN are not miscible.

EPR and Molecular Dynamics Study of Barstar-Barnase Interaction

Using spin labeling for studying protein macromolecules may reveal their significant dynamical and structural properties. EPR spectrum contains information about protein dynamics and internal motions, but, unfortunately, these are extremely versatile, and spectrum present only ‘digest’ of it. There is is an attractive way of joining Molecular Dynamics (MD) simulation with EPR. MD provides detailed system dynamics, and number of attempts has been made to calculate spectra directly from trajectory data. Still there is no currently reliable algorithm developed to date for this purpose.In this work, the study of complex formation between RNAse Barnase (Bn) and its specific inhibitor Barstar (Bs), is presented. High affinity of Bs to Bn, this protein pair is promising for creating large superstructures with controllable properties. Mutant C40A barstar labeled by C82 with 4-(2-chloromercuriphenyl)-2,2,5,5-tetramethyl-3-imidazoline-D3-1-oxyl, as well as its complex with Bn, was previously studied by X-band EPR to obtain correlation times for macromolecule Brownian diffusion and order parameters for internal dynamics.We built a model of labeled Bs, and BsBn complex, and ran a number of full-atom MD simulations. Both MD and EPR revealed two motional states of the spin label, one highly ordered, and another flexible in free Barstar. Detailed analysis of calculated data showed that difference between these two states was solely due to internal dynamics of the protein. Corresponding azimuthal order parameters calculated from MD trajectories well coincided with experimental ones, obtained from EPR spectra. It was found that formation of BsBn complex leads to complete disappearance of disordered state. Experimental evidence (provided by spin labeling) of key features observed in MD trajectories provide a validation of used parameters and protocols therefore.

Variation of Weak Polyelectrolyte Persistence Length through an Electrostatic Contour Length

There is currently no consensus that the classical perspective of electrostatic persistence length (the so-called Odijk–Skolnick–Fixman, or OSF, formulation), derived by equating changes in electrostatic energy with bending rigidity, is applicable to weak polyelectrolytes. Here, with a focus on polyelectrolyte chains of finite length at a single scale, we formulate a simple and general theoretical model featuring the electrostatic persistence length, Pe, through the introduction of an electrostatic contour length, Le, such that the electrostatic energy balance is applicable to highly flexible charged polyelectrolytes (where the intrinsic stiffness, P0 is on the order of Pe). To isolate the effect of ionization, only the salt-free regime is considered. At the upper limit (relatively rigid molecules), the new formulation converges to the classical OSF form, while the lower bound (highly flexible molecules) approaches proportionality to the Debye screening length, κ–1. In general, the electrostatic persistence can be described retroactively by the Debye screening, κ–1, and the ratio of electrostatic to intrinsic contour lengths, A/a, complementary to predictive theoretical formulations. The theory is validated via full atomistic molecular dynamics simulations of single, isolated model weak polyelectrolyte chains in explicit solvent—specifically poly(acrylic acid), PAA, and poly(allylamine hydrochloride), PAH, both of which undergo significant increases in persistence length under ionization. An ensemble of equilibrated polymer states is obtained via temperature assisted sampling, implementing molecular dynamics to drive the polymers into physically accessible conformations via cyclical temperature fluctuations and equilibration.

Comparative Dynamics of NMDA- and AMPA-Glutamate Receptor N-Terminal Domains

SummaryIonotropic glutamate receptors (iGluRs) harbor two extracellular domains: the membrane-proximal ligand-binding domain (LBD) and the distal N-terminal domain (NTD). These are involved in signal sensing: the LBD binds L-glutamate, which activates the receptor channel. Ligand binding to the NTD modulates channel function in the NMDA receptor subfamily of iGluRs, which has not been observed for the AMPAR subfamily to date. Structural data suggest that AMPAR NTDs are packed into tight dimers and have lost their signaling potential. Here, we assess NTD dynamics from both subfamilies, using a variety of computational tools. We describe the conformational motions that underly NMDAR NTD allosteric signaling. Unexpectedly, AMPAR NTDs are capable of undergoing similar dynamics; although dimerization imposes restrictions, the two subfamilies sample similar, interconvertible conformational subspaces. Finally, we solve the crystal structure of AMPAR GluA4 NTD, and combined with molecular dynamics simulations, we characterize regions pivotal for an as-yet-unexplored dynamic spectrum of AMPAR NTDs.

Interfacial properties of free-standing poly(3-hexylthiophene) films

Using full atomistic classical molecular dynamics simulations, the interfacial properties of free-standing poly(3-hexylthiophene) (P3HT) films have been investigated. The orientations of different parts of the P3HT chain and the surface tensions of the films were calculated in a temperature range of 540 K-600 K. At the liquid/vacuum interface, the P3HT chain shows ordering by exposing hexyl groups at the interface, while the chain backbone lays flat with the thiophene ring preferentially tilt toward the surface. At the interface, the terminal methyl groups of hexyl side chains are in excess compared to the methylene groups or thiophene rings. The surface tension of P3HT in its melt state shows similar temperature dependence to that of polymers that have long alkyl side chains. The surface tension values are comparable to those polymers that expose methyl or methylene groups on the surface. The surface tension values determined for the melt state are lower than the experimental reported values for crystalline P3HT films, as expected.

Damage of DNA backbone by nanoscale shock waves

By means of full-atom molecular dynamics simulations we investigate the process of DNA backbone damage by nanoscale shock waves in a water environment. These shock waves are created by ions penetrating the medium with high linear energy transfer. The high rate of the ions' energy transfer to the surrounding molecules leads to the rapid increase of the temperature in the vicinity of the ion trajectory, which causes the formation of shock waves propagating through the medium. We have investigated the ions' linear energy transfer of 900, 2000 and 5000 eV/nm. In the case of a linear energy transfer of 5000 eV/nm the deposition exerts unsustainable stress onthe DNA molecule, which leads to the breakage of DNA backbone covalent bonds by thermomechanical effects.

Dendrimer building toolkit: Model building and characterization of various dendrimer architectures

We have developed a graphical user interface based dendrimer builder toolkit (DBT) which can be used to generate the dendrimer configuration of desired generation for various dendrimer architectures. The validation of structures generated by this tool was carried out by studying the structural properties of two well known classes of dendrimers: ethylenediamine cored poly(amidoamine) (PAMAM) dendrimer, diaminobutyl cored poly(propylene imine) (PPI) dendrimer. Using full atomistic molecular dynamics (MD) simulation we have calculated the radius of gyration, shape tensor and monomer density distribution for PAMAM and PPI dendrimer at neutral and high pH. A good agreement between the available simulation and experimental (small angle X-ray and neutron scattering; SAXS, SANS) results and calculated radius of gyration was observed. With this validation we have used DBT to build another new class of nitrogen cored poly(propyl ether imine) dendrimer and study it's structural features using all atomistic MD simulation. DBT is a versatile tool and can be easily used to generate other dendrimer structures with different chemistry and topology. The use of general amber force field to describe the intra-molecular interactions allows us to integrate this tool easily with the widely used molecular dynamics software AMBER. This makes our tool a very useful utility which can help to facilitate the study of dendrimer interaction with nucleic acids, protein and lipid bilayer for various biological applications.

Effect of monomeric sequence on transport properties of d-glucose and ascorbic acid in poly(VP-co-HEMA) hydrogels with various water contents: molecular dynamics simulation approach

We have used full-atomistic molecular dynamics (MD) simulations of both random and blocky sequence hydrogel networks of poly(N-vinyl-2-pyrrolidone-co-2-hydroxyethyl methacrylate) (P(VP-co-HEMA)) with a composition of VP/HEMA = 37:13 to investigate the effect of the monomeric sequence and the water content on the transport properties of ascorbic acid and d-glucose at 310.15 K. The degrees of randomness of the monomer sequence for the random and the blocky copolymers were 1.170 and 0.104, respectively, and the degree of polymerization was fixed at 50. By analyzing the pair correlation functions, it was found that for both monomeric sequences, the guest molecules (i.e., ascorbic acid and d-glucose) have greater accessibility to the VP units than to the HEMA units due to the higher hydrophilicity of VP compared to HEMA units. While the monomeric sequence effect on the P(VP-co-HEMA) hydrogel is clearly observed with 20 wt. % water content, the effect is significantly reduced with 40 wt. % water content and disappears completely with 80 wt. % water content. This is because the hydrophilic guest molecules are more likely to be associated with water molecules than with the polymer network at the high water content. By analyzing the diffusion of the guest molecules and the inner-surface area, it is also found that the guest molecules are confined in the system at 20 wt. % water content, resulting in highly anomalous sub-diffusion. Therefore, at low water content, the diffusion of the guest molecules in the hydrogel is directly affected by the monomeric sequence through the interaction of guest molecules with the monomeric units, whereas such monomeric sequence effects are significantly reduced with increasing water content.

Molecular Modelling of G Protein-Coupled Receptors Through the Web.

With the recent crystallization of several G Protein-Coupled receptors (GPCRs), homology modelling and all atom molecular dynamics (MD) simulations have proven their usefulness for exploring the structure and function of this superfamily of membrane receptors. Subsequently, automated computational protocols have been implemented as web-based servers in the recent years to produce reliable models of GPCRs, providing partial or global solutions for the structural characterization and molecular simulation of GPCRs. These dedicated modelling services represent an attractive tool for the broader community of public researchers and pharmaceutical companies, in order to assist in the structure-based drug design of GPCRs. We here collect and analyze the existing web servers, among which a previously unreported service, GPCR-ModSim, offers for the first time full atom MD simulations in the pipeline for GPCR molecular modelling.

Thermomechanical damage of nucleosome by the shock wave initiated by ion passing through liquid water

We report on the results of full-atom molecular dynamics simulations of the heat spike in the water medium caused by the propagation of the heavy ion in the vicinity of its Bragg peak. High rate of energy transfer from an ion to the molecules of surrounding water environment leads to the rapid increase of the temperature of the molecules in the vicinity of ions trajectory. As a result of an abrupt increase of the temperature we observe the formation of the nanoscale shock wave propagating through the medium. We investigate the thermomechanical damage caused by the shock wave to the nucleosome located in the vicinity of heavy ion trajectory. We observe the substantial deformation of the DNA secondary structure. We show that the produced shock wave can lead to the thermomechanical breakage of the DNA backbone covalent bonds and present estimates for the number of such strand brakes per one cell nucleus.

Nucleation and Growth of Stellated Gold Clusters: Experimental Synthesis and Theoretical Study

An experimental and theoretical study on the structure and energetics of stellated gold clusters at several sizes is presented. Systematic molecular dynamics simulations on Kepler−Poisont classified clusters are performed based on cuboctahedral and icosahedral cores, following present and previous studies that suggest that stellated clusters grew from these seeds. For cluster sizes up to 10802 atoms, full atomistic molecular dynamics simulations at room temperature have been carried out. Results show that stellated clusters in the bigger size regime maintain their star-like shape at room temperature, and by means of linear fitting of energy data to proper function models, it is predicted that the two types of stellated structures might coexist at room temperature for relatively large sizes, these findings being in good agreement with experimental results.