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At least 793 records · Page 44Linked to original sources
PubMed1996

Conformational studies on the selectin and natural killer cell receptor ligands sulfo- and sialyl-lacto-N-fucopentaoses (SuLNFPII and SLNFPII) using NMR spectroscopy and molecular dynamics simulations. Comparisons with the nonacidic parent molecule LNFPII.

This investigation is focused on the conformational behavior of the blood group Lewisa (Le(a)-active pentasaccharide lacto-N-fucopentaose II (LNFPII) and its sulfated and sialylated analogs, SuLNFPII and SLNFPII. The latter two are more potent oligosaccharide ligands for the animal lectins, E- and L-selectin, and the natural killer cell receptor, NKR-P1, than are the shorter chain analogs based on the trisaccharide Le(a) domain. We report here that the three oligosaccharides based on the fucopentasaccharide have very similar average solution conformations as determined from NMR spectroscopical parameters, in particular 13C chemical shift differences. From restrained simulated annealing and restrained molecular dynamics (MD) simulations performed in order to determine the most probable conformational distributions around the glycosidic linkages we derive models for these oligosaccharides that are in good agreement with experimental parameters, such as rotating-frame Overhauser effects (ROE's) and long-range 1H,13C coupling constants across the glycosidic linkages. In these model structures the Le(a) domain at the non-reducing end of the longer chain oligosaccharides approximates the same rigid structure as in the shorter analogs. The Gal beta 1-4Glc linkage at the reducing end is also rather rigid, showing only little more flexibility than the Le(a) domain. However, the NeuAc alpha 2-3Gal linkage in SLNFPII, and the GlcNAc beta 1-3Gal linkage in all three oligosaccharides are flexible, in each case fluctuating mainly between two minimum energy structures: (phi = -81 degrees, psi = 8 degrees) and (phi = -160 degrees, psi = -20 degrees) for the NeuAc alpha 2-3Gal linkage, as reported previously for the isomeric sequence 3'-sialyl Le(x), and (phi = -25 degrees, psi = -26 degrees) and (phi = 20 degrees, psi = 24 degrees) for the GlcNAc beta 1-3Gal linkage. The flexibility of the latter linkage may allow the lactosyl domain at the reducing end to fit with little strain into extended carbohydrate binding sites on the recognition proteins, and, for the purposes of drug designs, it will be important to establish which conformational distribution is assumed for the GlcNAc beta 1-3Gal linkage in these longer chain oligosaccharides in the bound state.

Animals↗
PubMed2002

Molecular dynamics simulation of the association of nonpolar spheres in water.

We apply molecular dynamics (MD) simulations to the study of the association of nonpolar spheres of effective radii between 1.6 and 6.1 A dissolved in water. The constrained MD method is used to calculate the potential of mean force (PMF) of the interaction between spheres. The depth of the potential of mean force increases with increasing radius of the nonpolar sphere. Our results suggest that the PMF is largely governed by size or entropic effects, and that energetic effects associated with the breaking or distortion of hydrogen bonds are of minor importance.

Journal Article↗
PubMed2005

Principles of carbopeptoid folding: a molecular dynamics simulation study.

The conformational spaces of five oligomers of tetrahydrofuran-based carbopeptoids in chloroform and dimethyl sulfoxide were investigated through nine molecular dynamics simulations. Prompted by nuclear magnetic resonance experiments that indicated various stable folds for some but not all of these carbopeptoids, their folding behaviour was investigated as a function of stereochemistry, chain length and solvent. The conformational distributions of these molecules were analysed in terms of occurrence of hydrogen bonds, backbone torsional-angle distributions, conformational clustering and solute configurational entropy. While a cis-linkage across the tetrahydrofuran ring favours right-handed helical structures, a trans-linkage results in a larger conformational variability. Intra-solute hydrogen bonding is reduced with increasing chain length and with increasing solvent polarity. Solute configurational entropies confirm the picture obtained: they are smaller for cis- than for trans-linked peptides, for chloroform than for dimethyl sulfoxide as solvent and for shorter peptide chains. The simulations provide an atomic picture of molecular conformational variability that is consistent with the available experimental data.

Computer Simulation↗
PubMed2003

New insights into the Jahn-Teller effect through ab initio quantum-mechanical/molecular-mechanical molecular dynamics simulations of CuII in water.

The CuII hydration shell structure has been studied by means of classical molecular dynamics (MD) simulations including three-body corrections and hybrid quantum-mechanical/molecular-mechanical (QM/MM) molecular dynamics (MD) simulations at the Hartree-Fock level. The copper(II) ion is found to be six-fold coordinated and [Cu(H2O)6]2+ exhibits a distorted octahedral structure. The QM/MM MD approach reproduces correctly the experimentally observed Jahn-Teller effect but exhibits faster inversions (< 200 fs) and a more complex behaviour than expected from experimental data. The dynamic Jahn-Teller effect causes the high lability of [Cu(H2O)6]2+ with a ligand-exchange rate constant some orders or magnitude higher than its neighbouring ions NiII and ZnII. Nevertheless, no first-shell water exchange occurred during a 30-ps simulation. The structure of the hydrated ion is discussed in terms of radial distribution functions, coordination numbers, and various angular distributions and the dynamical properties as librational and vibrational motions and reorientational times were evaluated, which lead to detailed information about the first hydration shell. Second-shell water-exchange processes could be observed within the simulation time scale and yielded a mean ligand residence time of approximelty 20 ps.

Journal Article↗
PubMed2001

Molecular dynamics simulation reveals conformational switching of water-mediated uracil-cytosine base-pairs in an RNA duplex.

A 4 ns molecular dynamics simulation of an RNA duplex (r-GGACUUCGGUCC)(2 )in solution with Na+ and Cl- as counterions was performed. The X-ray structure of this duplex includes two water-mediated uracil-cytosine pairs. In contrast to the other base-pairs in the duplex the water-mediated pairs switch between different conformations. One conformation corresponds to the geometry of the water-mediated UC pairs in the duplex X-ray structure with water acting both as hydrogen-bond donor and acceptor. Another conformation is close to that of a water-mediated UC base-pair found in the X-ray structure of the 23 S rRNA sarcin/ricin domain. In this case the oxygen of the water molecule is linked to two-base donor sites. For a very short time also a direct UC base-pair and a further conformation that is similar to the one found in the RNA duplex structure but exhibits an increased H3(U)...N3(C) distance is observed. Water molecules with unusually long residence times are involved in the water-mediated conformations. These results indicate that the dynamic behaviour of the water-mediated UC base-pairs differs from that of the duplex Watson-Crick and non-canonical guanine-uracil pairs with two or three direct hydrogen bonds. The conformational variability and increased flexibility has to be taken into account when considering these base-pairs as RNA building blocks and as recognition motifs.

Base Pairing↗
PubMed1997

Molecular dynamics simulation of a dye molecule in the interior of a bilayer: 1,6-diphenyl-1,3,5-hexatriene in dipalmitoylphosphatidylcholine.

A molecular dynamics simulation was carried out for a dipalmitoylphosphatidylcholine (DPPC) membrane in its liquid crystalline state containing different concentrations of the dye molecule 1,6-diphenyl-1,3,5-hexatriene (DPH). From a numerical analysis of the trajectories, we obtained information concerning structural changes of the membrane due to the presence of the probe and some hydrodynamic information concerning the probe itself. The hydrodynamic properties regarding dye molecules that have been reported in this article are: rotational and translational diffusion coefficient and relaxation times. From this analysis, we estimated a range of values of 0.6-0.9 cP for the micro-viscosity in the mid-membrane. These simulations also afforded us some information regarding structural changes in the membrane as a consequence of the presence of the fluorescent dyes at different concentrations. Thus, the disorder inside the membrane, the surface area per lipid and thickness of the membrane were also investigated.

Journal Article↗
PubMed1988

Molecular dynamics simulations of ribonuclease T1: analysis of the effect of solvent on the structure, fluctuations, and active site of the free enzyme.

Molecular dynamics simulations were performed on ribonuclease T1 (RNase T1; EC 3.1.27.3) to determine a structure for the free enzyme. Simulations starting with the X-ray coordinates for the 2'GMP-RNase T1 complex were done in vacuo and with an 18-A water ball around the active site using stochastic boundary conditions to understand the influence of water on both the structure and fluctuations of the enzyme. Removal of 2'GMP caused structural changes in the loop regions, including those directly interacting with the bound inhibitor in the crystal structure, while regions of secondary structure were less affected. The presence of solvent in the simulation damped the structural changes observed, which may be related to the use of full charges in both simulations. Fluctuations were also affected by the water, which generally increased both at the surface and in the interior of the protein. The active site in vacuo collapsed upon itself, forming a number of protein-protein hydrogen bonds leading to larger structural changes and lowered fluctuations while the presence of water kept the active site open, minimized structural changes, and increased fluctuations. Such fluctuations in the active site may be important for the binding of inhibitors or substrates to the enzyme. Lastly, results from the water simulation allow the prediction of a motion for a hypothetical tryptophan at position 45, which can ultimately be tested experimentally via time-resolved fluorescence using a site-specific mutant of the enzyme.

Aspergillus oryzae↗
PubMed2004

Investigation of the microstructure of micelles formed by hard-sphere chains interacting via size nonadditivity by discontinuous molecular dynamics simulation.

Micelle formation by short nonadditive hard surfactant chains was investigated at different size ratios, reduced densities, and nonadditivity parameters using molecular dynamics simulation. It was found that spherical, cylindrical, lamellar, and reverse micelles can form in systems with different head, tail, and solvent characteristics. Hard-core surfactant chains composed of a head segment and three tail segments were simulated in a solvent of hard spheres. The formation of micelles was found to be a strong function of the packing fraction and nonadditivity parameter. Micelles were more stable at higher densities and larger nonadditivity parameters. At lower densities, micelles tended to break into small, dynamic globules.

Computer Simulation↗
PubMed2006

Adsorption of polycyclic aromatic hydrocarbons at the air-water interface: molecular dynamics simulations and experimental atmospheric observations.

Adsorption of benzene, naphthalene, anthracene, and phenanthrene at the aqueous surface is investigated by means of molecular dynamics simulations. Potentials of mean force, i.e., free energy profiles obtained when moving the studied molecules across an aqueous slab were evaluated. In all cases, deep surface free energy minima, corresponding to orders of magnitude of surface enhancement of the aromatic molecule, were located. This enhancement, which increases with the size of the solute, points to the importance of the aqueous surface for the chemistry of polycyclic aromatic hydrocarbons (PAHs). Supporting evidence in the atmospheric environment related to the heterogeneous chemistry of PAHs on water droplets and planar surfaces is summarized. There is good agreement between the hydration free energies computed from MD calculations and the experimentally determined values. Data pertaining to the importance of the air-water interface in the adsorption and transport of PAHs on micron sized water droplets are described. The relevant data on adsorption and reaction (ozonation and photochemical) at the air-water interface of planar surfaces and droplets are also summarized.

Adsorption↗
PubMed2004

Molecular dynamic simulations of atom-cluster collision processes.

Monomer-cluster collisions of Lennard-Jones argon atoms have been studied using molecular dynamics simulation for target cluster sizes of 2, 3, 4, 5, 10, and 20 atoms. Capture probability of monomers by clusters and the lifetimes of the resulting clusters have been calculated as a function of impact parameter and the total energy of the target cluster. Cluster lifetime is further integrated over all impact parameters to obtain the average lifetime for each cluster size and energy. The average lifetime of the smallest aggregates is shown to be short compared to the collision time between monomers and clusters unless the vapor is highly supersaturated. The formation probability of a new cluster decreases steeply if a minimum lifetime is required for the cluster.

Journal Article↗
PubMed2006

Phase transitions of methane using molecular dynamics simulations.

Using a short ranged Lennard-Jones interaction and a long ranged electrostatic potential, CH4 under high pressure was modeled. Molecular dynamics simulations on small clusters (108 and 256 molecules) were used to explore the phase diagram. Regarding phase transitions at different temperatures, our numerical findings are consistent with experimental results to a great degree. In addition, the hysteresis effect is displayed in our results.

Journal Article↗
PubMed2006

Nonequilibrium molecular dynamics simulation study on the orientation transition in the amphiphilic lamellar phase under shear flow.

By the extensive large-scale nonequilibrium molecular dynamics simulation on an effective generic model-A2B2 tetramer for amphiphiles, we investigate the shear-induced parallel to perpendicular orientation transition in the lamellar phase as a function of segregation degree and shear rate. Under low rate shear flow the evolution of parallel lamellar configurations at different segregation strengths shows a similar kinetic pathway independent of the segregation degree. While under high rate shear flow in which the lifetime of undulation instability exceeds the characteristic time of the applied shear flow, the kinetic pathway of the shear-induced parallel-to-perpendicular orientation transition in lamellar systems is the segregation degree dependent. Comparing the temporal mesoscopic domain morphology, the microscopic chain conformation, and macroscopic observable-viscosity changes with the experimentally proposed mechanisms, we find that the undulation instability, partial breakup of monodomain, grain rotation, and recombination combined with defect migration and annihilation are the kinetic pathway for the parallel-to-perpendicular orientation transition in the lamellar phase in or near the intermediate segregation limit, and that the undulation instability, domain dissolution, and reformation along the preferred direction combined with defect migration and annihilation are the kinetic pathway for the parallel-to-perpendicular orientation transition in the lamellar phase close to the order-to-disorder phase transition point. A detailed underlying microscopic picture of the alignment process illustrates that the orientation transition is driven by the alignment of molecules with shear flow. The orientation diagram that characterizes the steady-state orientations as a function of shear rate and attractive potential depth is built, in which the attractive potential depth takes the role of an inverse temperature, somewhat like the Flory-Huggins interaction parameter. The microscopic mechanism of the critical orientation transition condition is discussed.

Journal Article↗
PubMedDate not supplied

Modelling of ion permeation in K+ channels by nonequilibrium molecular dynamics simulations: I. Permeation energetics and structure stability.

Because of the great importance of physiological and pathophysiological processes in which ion channels are involved and because their operation is described by physicochemical laws, there have been many attempts to develop physical models able to describe the membrane permeability and also the structural and functional properties of the channel protein structures. In this study (in two parts) we present a series of simulations on a K+ channel model (KcsA) using Nonequilibrium Molecular Dynamics simulations (NEMD), in order to follow structure stability, permeation energetics and the possibility of obtaining quantitative information about the permeation process using the Linear Response Theory (LRT). On K+ ions were applied external forces to determine them to pass through the channel in a relatively small amount of time, accessible computationally. We ascertained a high resistance of the protein to deformation even in conditions when great forces were applied on ions (the system was far from equilibrium). The estimation of energy profiles in the course of ions passage through the channel demonstrates that these proteins create a conductivity pathway with no energetic barriers for ions movement across the channel (which could be present due to ions dehydration). The dynamic model used demonstrates (as proposed before in the literature after the examination of the static KcsA structure obtained by X-Ray crystallography) that this is due to the interaction of ions with the negatively charged carbonyl oxygens of the main polypeptide chain in the selectivity filter region.

Computer Simulation↗
PubMed1997

Binding pathway of retinal to bacterio-opsin: a prediction by molecular dynamics simulations.

Formation of bacteriorhodopsin (bR) from apoprotein and retinal has been studied experimentally, but the actual pathway, including the point of entry, is little understood. Molecular dynamics simulations provide a surprisingly clear prediction. A window between bR helices E and F in the transmembrane part of the protein can be identified as an entry point for retinal. Steered molecular dynamics, performed by applying a series of external forces in the range of 200-1000 pN over a period of 0.2 ns to retinal, allows one to extract this chromophore from bR once the Schiff base bond to Lys216 is cleaved. Extraction proceeds until the retinal tail forms a hydrogen bond network with Ala144, Met145, and Ser183 side groups lining the exit/entry window. The manipulation induces a distortion with a fitted root mean square deviation of coordinates (ignoring retinal, water, and hydrogen atoms) of less than 1.9 A by the time the retinal carbonyl reaches the protein surface. The forces needed to extract retinal are due to friction and do not indicate significant potential barriers. The simulations therefore suggest a pathway for the binding of retinal. Water molecules are found to play a crucial role in the binding process.

Bacteriorhodopsins↗
PubMed2006

Molecular dynamics simulations of Hydrogenobacter thermophilus cytochrome c552: comparisons of the wild-type protein, a b-type variant, and the apo state.

Molecular dynamic simulations have been performed for wild-type Hydrogenobacter thermophilus cytochrome c(552), a b-type variant of the protein, and the apo state with the heme prosthetic group removed. In the b-type variant, Cys 10 and Cys 13 were mutated to alanine residues, and so the heme group was no longer covalently bound to the protein. Two 8-ns simulations have been performed for each system at 298 and 360 K. The simulations of the wild-type protein at 298 K show a very close agreement with experimental NMR data. A fluxional process involving the side chain of Met 59, which coordinates to the heme iron, is observed in accord with proposals from NMR studies. Overall, the structure and dynamical behavior of the protein during the simulations of the b-type variant is closely similar to that of the wild-type protein. However, side chains in the heme-binding site show larger fluctuations in the b-type variant simulation at 360 K. In addition, structural changes are seen for a number of residues close to the heme group, particularly Gly 22 and Ser 51. The simulations of the apo state show significant conformational changes for residues 50-59. These residues form a loop region, which packs over the heme group in the wild-type protein and hydrogen bonds to the heme propionate groups. In the absence of heme, in the apo state simulations, these residues form short but persistent regions of beta-sheet secondary structure. These could provide nucleation sites for the conversion to amyloid fibrils.

Alanine↗
PubMed1992

A 500 ps molecular dynamics simulation study of interleukin-1 beta in water. Correlation with nuclear magnetic resonance spectroscopy and crystallography.

We report the results of a 500 ps molecular dynamics simulation of the cytokine interleukin-1 beta, a protein of 153 amino acids, immersed in a sphere of 3783 bulk water molecules with a radius of 33 A. The simulation reproduces the amplitudes of the fast librational motions of the backbone N-H bonds determined from 15N nuclear magnetic relaxation data, as well as the crystallographic B-factors. Moreover, this study suggests a molecular picture of the nature of the slow internal motions that have been inferred from nuclear magnetic resonance relaxation experiments. These experiments indicated that, in addition to fast motions common to all residues, 32 surface residues exhibit slow motions on the 400 ps to 5 ns time-scale. While the present simulation is not sufficiently long to provide a quantitative description of events on this time-scale, it is long enough to observe several large amplitude transitions that are likely candidates for these slow motions. Specifically, in many of these 32 residues, the N-H groups are hydrogen bonded and infrequent dihedral transitions cause the N-H vectors to jump between states with well-defined orientations. It is shown that the time course of the angular reorientational correlation functions of these residues calculated from the trajectory is a reflection of the random times at which these infrequent jumps happen to have occurred. Thus, while the rate of these transitions cannot be quantified, the simulated decay of these correlation functions is completely consistent with the physical picture in which the N-H vectors, in addition to fast librational motion, undergo large amplitude jumps between conformations stabilized by hydrogen bonds.

Computer Simulation↗
PubMed1997

Search for rigid sub domains in DNA from molecular dynamics simulations.

A strategy is presented for searching which atoms can be regrouped within rigid sub-units during the time course of Molecular Dynamics simulations of biopolymers. The root mean square fluctuations of the interatomic distances are used as a criterion. The number of rigid sub-units which are found depends on the tolerance rc for the definition of a rigid body, i.e. until which value the fluctuations can be neglected. The method is applied to two self-complementary oligonucleotides belonging to the B-form family which give identical results. With rc = 0.027 nm each nucleotide may be described as 3 rigid sub-units: the sugar ring, the base and the backbone (PO4 + C5' atoms). With rc = 0.01 nm, the same sub-units are obtained except that C5' can no more be regrouped with the PO4 atoms. It is shown that the variation of the coulombic potential owing to the deformation of the sub-units during the time course of the simulation is on the same order of magnitude as the inaccuracy due to the choice of the force field parameters.

Computer Simulation↗