Molecular Dynamics Simulations of Phosphorylated Intrinsically Disordered Proteins: A Force Field Comparison

Phosphorylation is a common post-translational modification among intrinsically disordered proteins and regions, which helps regulate function by changing the protein conformations, dynamics, and interactions with binding partners. To fully comprehend the effects of phosphorylation, computer simulations are a helpful tool, although they are dependent on the accuracy of the force field used. Here, we compared the conformational ensembles produced by Amber ff99SB-ILDN+TIP4P-D and CHARMM36m, for four phosphorylated disordered peptides ranging in length from 14–43 residues. CHARMM36m consistently produced more compact conformations with a higher content of bends, mainly due to more stable salt bridges. Based on comparisons with experimental size estimates for the shortest and longest peptide, CHARMM36m appeared to overestimate the compactness. The difference between the force fields was largest for the peptide showing the greatest separation between positively charged and phosphorylated residues, in line with the importance of charge distribution. For this peptide, the conformational ensemble did not change significantly upon increasing the ionic strength from 0 mM to 150 mM, despite a reduction of the salt-bridging probability in the CHARMM36m simulations, implying that salt concentration has negligible effects in this study.     

Force field generation and molecular dynamics simulations of Li-Nafion

A new molecular dynamics force field for Nafion^® containing Li⁺ ions has been generated using Density Functional Theory calculations (B3LYP) on a Nafion side-chain, a Li⁺ ion and a H₂O molecule. The depth of the potential energy well between Li⁺ and the sulphonate group was decreased with ∼10 kcal/mol and the optimal Li-S distance 0.5 Å shorter, as compared to force fields generated without water present. Molecular dynamics simulations based on the new force field result in a self-diffusion coefficient for Li⁺ of 8.0 × 10⁻⁸ cm²/s at 353 K, which is closer to experimental result than previous simulations using force fields based on pure Nafion-cation interactions.     

Theoretical Determination of Molecular Structure and Conformation. XI. The Puckering of Oxolanes

Structural, conformational and energetic properties of cyclopentane (1) and the seven oxolanes monoxolane (2), 1,3-dioxolane (3), 1,2-dioxolane (4), 1,2,4-trioxolane (5), 1,2,3-trioxolane (6), tetroxolane (7), and pentoxolane (8) are investigated employing the polarized 6-31G* basis set at the Hartree-Fock level of theory. Extensive geometry optimization is carried out within the model of the semirigid pseudorotor. The conformational potentials V of compounds 1–8 are evaluated as a function of the puckering amplitude q and the pseudorotation phase angle Φ. Ring molecules 1 and 8 are free pseudorotors, while pseudorotation is hindered by barriers ≤ 3.3 kcal/mol for oxolanes 2–7. Puckering and inversion barriers increase with the number of O-O bonds but decrease with the number of ether bridges. Puckered C₂-symmetrical twist forms are the most stable conformations for compounds 2–7 but 6, where highest stability is found for the C₂-symmetrical envelope forms. At room temperature a multitude of conformers of 1–8 coexists either because of free pseudorotation (barriers < RT) or large amplitudes of pseudolibration. These results are rationalized in terms of the rotor potentials of appropriate reference compounds (C₂H₆, CH₃OH, H₂O₂). A more elegant approach leads to a simple π electron count and an analysis of bonding and antibonding overlap in the π-type HOMO's. In this way the effects of substituents can be predicted and conformational preferences of the furanose ring in nucleotides, nucleosides and carbohydrates explained. The relative stability of the oxolanes is analyzed by calculating O-O bond energies, bond-bond interactions and ring strain for each compound. The lability of the higher oxolanes is traced back to increased ring strain. A new method of the conformational analysis of ring compounds is outlined.     

Conformational transition characterization of glass transition behavior of polymers

The conformational transition behavior of polymer in the amorphous state has been investigated through molecular dynamics simulations across the glass transition temperature (T_g). We find that the conformational transition, a localized and short time dynamics feature, crosses over different barrier heights when the system transforms from the molten state into the glass state and the barrier height in the glass state is markedly lower than that above T_g. In addition to the overall transition behavior, the specific transitions between the rotational isomeric states (RIS) g⁺, t⁻, t⁺ and g⁻ are also investigated in detail. The populations of these specific transitions undergo considerable changes when the temperature decreases; meanwhile, the larger transition rates of the ending torsions get diminished. Besides the rate, the rotation degrees of the dihedrals during the transitions also change their distributions tremendously through T_g, below which most of the larger transition angles (50-100°) were inhibited remaining those sharply around 30°. This possibly explains why below T_g the conformational transition process has a lower effective barrier.     

Molecular dynamics simulations of polyphosphazenes: poly[bis(chloro)phosphazene][NPCl2] n

Suitable parameter sets for the CHARMm force field were derived for the structural units in polychlorophosphazene [P=N, P N, P Cl] using the Dinur Hagler energy second derivative procedure based on quantum mechanical SCI calculations using the 6–31G^* basis set. To validate the reliability of the parameter set, structural results obtained with CHARMm for the adopted model compounds (OP₂NCl₅ and OP₃N₂Cl₅) were compared with those derived fromab initio quantum mechanics using the 6–31G^* basis set. Application of molecular dynamics (MD) simulations in combinatioin with the available X-ray diffraction data provided structural and conformational information on the polymer. The calculation made using the periodic boundary conditions (PBC) agree well with the polychlorophosphazene ordered in a monoclinic unit cell (a=5.98,b=12.99,c=4.92 A; β=111.7). This model was stabilized mainly by the image atoms contribution to the electrostatic energy term and had aquasi-planar conformation of the backbone chain (glide symmetry). The MD calculations also provided evidence that the difference between single and double PN bonds is less marked than that measured experimentally. This result is, however, in agreement with more recent and accurate X-ray studies on poly(methylphosphazene). Validation of the polymer model provided a complete picture, otherwise experimentally inaccessible, of the internal fluctuations of the polymeric chains.     

Force fields for classical atomistic simulations of small gas molecules in silicalite-1 for energy-related gas separations at high temperatures

High temperature (>573 K) molecular dynamics studies of gas diffusion in microporous zeolites require consideration of the zeolite framework flexibility. Pore windows can expand and contract at high temperatures, affecting phase space and material properties. No studies to date have addressed the application of the condensed-phase optimized molecular potentials for atomistic simulation studies or the consistent valence force field to simulate gas diffusion and adsorption in siliceous MFI (silicalite-1). The current study seeks to validate these intramolecular and intermolecular potentials along with another zeolite-specific force field reported by Nicholas et al. (JACS 113:4792–4800, 1991) for silicalite-1, one of the most extensively investigated zeolites, with respect to diffusion of several gas molecules. The experimental diffusion coefficients of H₂, CO₂, CH₄, O₂ and N₂ in silicalite-1 obtained using pulse-field gradient-nuclear magnetic resonance and quasi-elastic neutron scattering methods were compared to theoretically derived diffusion coefficients employing these force fields in molecular dynamics simulations. The diffusion coefficients obtained using the three force fields for H₂, CO₂, CH₄, O₂ and N₂ agreed well with these experimental data. The zeolite-specific force field of Nicholas et al. was employed in grand canonical Monte Carlo simulations to obtain adsorption isotherms of these gases. The adsorption isotherms and isosteric heats of adsorption predicted were also in agreement with the expected range of available experimental and theoretical adsorption data reported in the literature.     

Prediction of the self-diffusion coefficients in aqueous KCl solution using molecular dynamics: A comparative study of two force fields

Molecular dynamic simulation was used to calculate the self-diffusion coefficients of ions in aqueous KCl solution. The simulations were performed for enough time (12 ns) in the form of all-atom to determine the accurate values of the self-diffusion coefficients. The values of the self-diffusion coefficients were calculated by Einstein equation. Two different force fields of Dang and Deublein were employed in the simulations, and we found that at low ion concentration (equal or less than 3mol/(kg of H₂O)), the Dang force field is more accurate for prediction of the selfdiffusion coefficient of K⁺ ions and Deublein force field is more accurate for Cl^? ions. An Arrhenius type equation was used to model the temperature dependence of the self-diffusion coefficients and the diffusion activation energies at different ion concentrations were reported.     

Effect of liquid bridge evolution on the droplet non-coalescence under a DC electric field

The droplet non-coalescence characteristics and mechanism under a DC electric field are investigated by comprehensively using high-speed microscopic experiments, molecular dynamics simulations, and interface dynamics simulations. The researches show whether two droplets coalesce or not depends on the evolution of liquid bridge. The liquid bridge evolution is not only dominated by the electric force F_E and the capillary force F_i, but also slowed down by the viscous force. The relative strength of F_E and capillary force F_i relies on the electric capillary number Ca and the maximum liquid bridge radius R*_max. The droplet non-coalescence is more likely to happen as the Ca increases or the R*_max decreases. Furthermore, the critical value Ca_c for droplet non-coalescence reduces as the R*_max decreases. The ion transportation causes uneven distribution of ions and thus strengthens the F_E, resulting in the non-coalescence. These results provide significant guidance for efficient demulsification of water-in-oil emulsion.     

Molecular Dynamics Studies of Bacteriorhodopsin's Photocycles

The availability of the structure of bacteriorhodopsin from electron microscopy studies has opened up the possibility of exploring the proton pump mechanism of this protein by means of molecular dynamics simulations. In this review we summarize earlier theoretical investigations of the photocycle of bacteriorhodopsin including relevant quantum chemistry studies of retinal, structure refinement, molecular dynamics simulations, and evaluation of pK_a values. We then review a series of recent modeling efforts which refined the structure of bacteriorhodopsin adding internal water, and which studied the nature of the J intermediate and the likely geometry of the K₅₉₀ and L₅₅₀ intermediates (strongly distorted 13-cis) as well as the sequence of retinal geometry and protein conformational transitions which are conventionally summarized as the M₄₁₂ intermediate. We also review simulations of the photocycle of light-adapted bacteriorhodopsin at T=77 K and of the photocycle of dark-adapted bacteriorhodopsin, both cycles differing from the conventional photocycle through a nonfunctional (pure 13-cis) retinal geometry of the corresponding K₅₉₀ and L₅₅₀ states. The simulations demonstrate a potentially critical role of water and of minute reorientations of retinal's Schiff base nitrogen in controlling proton pumping in bR₅₆₈; the simulations also indicate the existence of heterogeneous photocycles. The results exemplify the important role of molecular dynamics simulations in extending investigations on bacteriorhodopsin to a level of detail which is presently beyond experimental resolution, but which needs to be known to resolve the pump mechanism of bacteriorhodopsin. Finally, we outline the major existing challenges in the field of bacteriorhodopsin modeling.     

Insights from NMR Spectroscopy into the Conformational Properties of Man‐9 and Its Recognition by Two HIV Binding Proteins

Man₉GlcNAc₂ (Man‐9) present at the surface of HIV makes up the binding sites of several HIV‐neutralizing agents and the mammalian lectin DC‐SIGN, which is involved in cellular immunity and trans‐infections. We describe the conformational properties of Man‐9 in its free state and when bound by the HIV entry‐inhibitor protein microvirin (MVN), and define the minimum epitopes of both MVN and DC‐SIGN by using NMR spectroscopy. To facilitate the implementation of 3D ¹³C‐edited spectra to deconvolute spectral overlap and to determine the solution structure of Man‐9, we developed a robust expression system for the production of ¹³C,¹⁵N‐labeled glycans in mammalian cells. The studies reveal that Man‐9 interacts with HIV‐binding proteins through distinct epitopes and adopts diverse conformations in the bound state. In combination with molecular dynamics simulations we observed receptor‐bound conformations to be sampled by Man‐9 in the free state, thus suggesting a conformational selection mechanism for diverse recognition.     

Influence of the adjustable parameters of the DPD on the global and local dynamics of a polymer melt

We present DPD simulations of linear polyethylene melts with force fields derived from microscopic simulations using the concept of potential of mean force. We aim at simulating realistic short polymers from a qualitative and quantitative point of view. An interesting issue is then to know the influence of the adjustable parameters of the DPD: γ, the friction coefficient, and r_C, the cut-off radius, on the global and local dynamics of the polymer, i.e., the diffusion coefficient, D_CM, the end-to-end decorrelation time, τ_R and the Rouse times. By varying these two parameters, we investigate structural and dynamical properties for different polymeric systems at a given chain length. Although scaling laws typical of the Rouse model have been reproduced using this DPD method, we observe deviation from the Rouse theory for the local dynamics of certain systems. The dynamical properties of the polymer melt are defined simultaneously by γ and r_C. Therefore we combine these two parameters, introducing a new parameter, the effective friction coefficient, γ^eff.     

Thermal properties of poly(lactic acid) fumed silica nanocomposites: Experiments and molecular dynamics simulations

Poly(lactic acid) (PLA) fumed silica nanocomposites were prepared by twin-screw extruder. Thermal properties were investigated by experiments and molecular dynamics simulations. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were used and 1.34 °C increase of the glass transition temperature (T_g) and 12 °C improvement of thermal stability were observed for PLA–silica nanocomposites as compared to neat PLA. Molecular dynamics simulations (NPT ensemble) were carried out using modified OPLS-AA force field, and T_g and root-mean-square radii of gyration (R_g) were calculated. A good agreement between the simulation results and experiments was obtained.     

Conformational Transitions of the Amyloid-β Peptide Upon Copper(II) Binding and pH Changes

Amyloid-β (Aβ) is a natively unfolded peptide found in all Alzheimer's disease patients as the major component of fibrillar plaques, which are recognized as an important pathological hallmark in Alzheimer's disease. The binding of copper to Aβ increases its neurotoxicity, as Cu²⁺ causes Aβ to become redox active and decreases the lag time associated with Aβ aggregation. In addition, the pH is a major factor that influences both the Aβ aggregation rates and Cu²⁺ binding. Hamiltonian replica exchange molecular dynamics (H-REMD) simulations enable atomistic insights into the effects of pH and Cu²⁺ complexation on the structure and dynamics of Aβ. To study the Aβ_1–42/Cu²⁺ complex, we have developed new force-field parameters for the divalent copper ion ligated by the two histidine residues, His6 and His13, as well as the amine and carbonyl groups of Asp1, in a distorted square-planar geometry. Our comparative simulations reveal that both Cu²⁺ binding and a low pH-mimicking acidosis, linked to inflammatory processes in vivo, accelerate the formation of β-strands in Aβ_1–42 and lead to the stabilization of salt bridges, previously shown to promote Aβ aggregation. The results suggest that Cu²⁺ binding and mild acidic conditions can shift the conformational equilibrium towards aggregation-prone conformers for the monomeric Aβ.     

Insights from ab initio molecular dynamics simulations for a multicomponent oxide glass

It remains a challenge to establish structural models of multicomponent oxide glass systems. In this study, we have investigated 68.3SiO₂–16.1B₂O₃–4.2Al₂O₃–11.4Na₂O glass and melt structures by ab initio molecular dynamics (AIMD) simulations. The atomic configurations obtained from AIMD simulations were validated against ¹⁷O solid‐state NMR spectrum under 24.0 T and neutron diffraction data, and excellent agreement was achieved. The bond lengths, angles, and coordination geometries were statistically analyzed for each atomic species. Here we particularly address the role of minor atomic species such as five‐coordinate Si (Si^V) and Al (Al^V). The Si^V–O bond lengths and O–Si^V–O angle distribution in the glass indicated 1.718 Å and three peaks at 90°, 120°, and 175°, which are assigned to a coordination geometry of the trigonal bipyramidal structure. Ring statistic analysis revealed that Si^V and Al^V were found to preferentially contribute to the formation of small ring sizes.     

Molecular dynamics simulations of polyphosphazenes: poly[bis(chloro)phosphazene][NPCl2]n

Suitable parameter sets for the CHARMm force field were derived for the structural units in polychlorophosphazene [P=N, P N, P Cl] using the Dinur Hagler energy second derivative procedure based on quantum mechanical SCI calculations using the 6–31G^* basis set. To validate the reliability of the parameter set, structural results obtained with CHARMm for the adopted model compounds (OP₂NCl₅ and OP₃N₂Cl₅) were compared with those derived fromab initio quantum mechanics using the 6–31G^* basis set. Application of molecular dynamics (MD) simulations in combinatioin with the available X-ray diffraction data provided structural and conformational information on the polymer. The calculation made using the periodic boundary conditions (PBC) agree well with the polychlorophosphazene ordered in a monoclinic unit cell (a=5.98,b=12.99,c=4.92 A; =111.7). This model was stabilized mainly by the image atoms contribution to the electrostatic energy term and had aquasi-planar conformation of the backbone chain (glide symmetry). The MD calculations also provided evidence that the difference between single and double PN bonds is less marked than that measured experimentally. This result is, however, in agreement with more recent and accurate X-ray studies on poly(methylphosphazene). Validation of the polymer model provided a complete picture, otherwise experimentally inaccessible, of the internal fluctuations of the polymeric chains.Presented at the 1st Italian Workshop on Cyclo- and Poly(phosphazene) Materials, February 15–16, 1996, at the CNR Research Area in Padova, Italy.     

Monte Carlo simulations of phase behavior and microscopic structure for supercritical CO2 and thiophene mixtures

The phase equilibria of thiophene in supercritical carbon dioxide are calculated by Monte Carlo simulations in Gibbs ensemble using a united atom force field. To validate the simulations, binary vapor–liquid coexistence curves were computed for two different temperatures using Monte Carlo simulations. An excellent agreement between simulations and experimental data is obtained. The effects of pressure on structural properties were studied for thiophene–CO₂ binary mixtures. The radial distribution functions and local composition of thiophene in CO₂ were investigated over a range of pressures. A weak dependence of thiophene structural properties with pressure was observed in supercritical phase. Local solution structure of thiophene in supercritical CO₂ was studied by computing angular–radial distribution functions and spatial distribution functions with three-dimensional probability distributions. The characteristic angular–radial distributions show a mutually parallel arrangement between thiophene plane and CO₂ molecules within the first solvation shell. Spatial distribution functions (SDFs) results show that CO₂ molecules have two higher probability distributions around thiophene molecules located above and below the thiophene ring.     

Study on the Application of the Combination of TMD Simulation and Umbrella Sampling in PMF Calculation for Molecular Conformational Transitions

Free energy calculations of the potential of mean force (PMF) based on the combination of targeted molecular dynamics (TMD) simulations and umbrella samplings as a function of physical coordinates have been applied to explore the detailed pathways and the corresponding free energy profiles for the conformational transition processes of the butane molecule and the 35-residue villin headpiece subdomain (HP35). The accurate PMF profiles for describing the dihedral rotation of butane under both coordinates of dihedral rotation and root mean square deviation (RMSD) variation were obtained based on the different umbrella samplings from the same TMD simulations. The initial structures for the umbrella samplings can be conveniently selected from the TMD trajectories. For the application of this computational method in the unfolding process of the HP35 protein, the PMF calculation along with the coordinate of the radius of gyration (R_g) presents the gradual increase of free energies by about 1 kcal/mol with the energy fluctuations. The feature of conformational transition for the unfolding process of the HP35 protein shows that the spherical structure extends and the middle α-helix unfolds firstly, followed by the unfolding of other α-helices. The computational method for the PMF calculations based on the combination of TMD simulations and umbrella samplings provided a valuable strategy in investigating detailed conformational transition pathways for other allosteric processes.     

Investigations of the Binding of [Pt2(DTBPA)Cl2](II) and [Pt2(TPXA)Cl2](II) to DNA via Various Cross-Linking Modes

We have constructed models for a series of platinum-DNA adducts that represent the binding of two agents, [Pt₂(DTBPA)Cl₂](II) and [Pt₂(TPXA)Cl₂](II), to DNA via inter- and intra-strand cross-linking, and carried out molecular dynamics simulations and DNA conformational dynamics calculations. The effects of trans- and cis-configurations of the centers of these di-nuclear platinum agents, and of different bridging linkers, have been investigated on the conformational distortions of platinum-DNA adducts formed via inter- and intra-strand cross-links. The results demonstrate that the DNA conformational distortions for the various platinum-DNA adducts with differing cross-linking modes are greatly influenced by the difference between the platinum-platinum distance for the platinum agent and the platinum-bound N7–N7 distance for the DNA molecule, and by the flexibility of the bridging linkers in the platinum agent. However, the effects of trans/cis-configurations of the platinum-centers on the DNA conformational distortions in the platinum-DNA adducts depend on the inter- and intra-strand cross-linking modes. In addition, we discuss the relevance of DNA base motions, including opening, shift and roll, to the changes in the parameters of the DNA major and minor grooves caused by binding of the platinum agent.