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At least 1,729 records · Page 96Linked to original sources
PubMed2006

Structural transitions of confined model proteins: molecular dynamics simulation and experimental validation.

Proteins fold in a confined space not only in vivo, i.e., folding assisted by molecular chaperons and chaperonins in a crowded cellular medium, but also in vitro as in production of recombinant proteins. Despite extensive work on protein folding in bulk, little is known about how and to what extent the thermodynamics and kinetics of protein folding are altered by confinement. In this work, we use a Gō-like off-lattice model to investigate the folding and stability of an all beta-sheet protein in spherical cages of different sizes and surface hydrophobicity. We find whereas extreme confinement inhibits correct folding, a hydrophilic cage stabilizes the protein due to restriction of the unfolded configurations. In a hydrophobic cage, however, strong attraction from the cage surface destabilizes the confined protein because of competition between self-aggregation and adsorption of hydrophobic residues. We show that the kinetics of protein collapse and folding is strongly correlated with both the cage size and the surface hydrophobicity. It is demonstrated that a cage of moderate size and hydrophobicity optimizes both the folding yield and kinetics of structural transitions. To support the simulation results, we have also investigated the refolding of hen-egg lysozyme in the presence of cetyltrimethylammoniumbromide (CTAB) surfactants that provide an effective confinement of the proteins by micellization. The influence of the surfactant hydrophobicity on the structural and biological activity of the protein is determined with circular dichroism spectrum, fluorescence emission spectrum, and biological activity assay. It is shown that, as predicted by coarse-grained simulations, CTAB micelles facilitate the collapse of denatured lysozyme, whereas the addition of beta-cyclodextrin-grafted-PNIPAAm, a weakly hydrophobic stripper, dissociates CTAB micelles and promotes the conformational rearrangement and thereby gives an improved recovery of lysozyme activity.

Acrylic Resins↗
PubMed1998

Molecular modeling of HIV-1 coreceptor CCR5 and exploring of conformational space of its extracellular domain in molecular dynamics simulation.

The chemokine receptor CCR5 functions as a major fusion coreceptor for macrophage-tropic human immunodeficiency virus entry into cell. Here we report a three-dimensional model of CCR5 built using molecular modeling approach. Because the virus binds to extracellular domain of the receptor, special attention was given to conformational flexibility, hydrogen bonding, and environmental polarity properties of this protein part. Such data were obtained in the result of molecular dynamics study of the extracellular domain. It was shown that during the simulation the extracellular segments form a compact globular domain with numerous long-range hydrogen bonds between them. First loop of the receptor stays quite rigid while N-terminal region and loops 2, 3 are rather flexible. A number of amino acid residues disposed in unfavourable environment and, therefore, potentially involved in binding of CCR5 to viral glycoproteins and chemokines, was delineated. Comparison of the results with available experimental data permits a proposal that such residues in loop-1 and N-terminal part of the receptor are important for HIV-1 entry, while those in loops 2 and 3 participate in ligand binding. Perspectives of rational alteration of virus-binding activity of CCR5 are discussed.

Amino Acid Sequence↗
PubMed2004

A hydration study of (1-->4) and (1-->6) linked alpha-glucans by comparative 10 ns molecular dynamics simulations and 500-MHz NMR.

The hydration behavior of two model disaccharides, methyl-alpha-D-maltoside (1) and methyl-alpha-D-isomaltoside (2), has been investigated by a comparative 10 ns molecular dynamics study. The detailed hydration of the two disaccharides was described using three force fields especially developed for modeling of carbohydrates in explicit solvent. To validate the theoretical results the two compounds were synthesized and subjected to 500 MHz NMR spectroscopy, including pulsed field gradient diffusion measurements (1: 4.0. 10(-6) cm(2). s(-1); 2: 4.2. 10(-6) cm(2). s(-1)). In short, the older CHARMM-based force field exhibited a more structured carbohydrate-water interaction leading to better agreement with the diffusional properties of the two compounds, whereas especially the alpha-(1-->6) linkage and the primary hydroxyl groups were inaccurately modeled. In contrast, the new generation of the CHARMM-based force field (CSFF) and the most recent version of the AMBER-based force field (GLYCAM-2000a) exhibited less structured carbohydrate-water interactions with the result that the diffusional properties of the two disaccharides were underestimated, whereas the simulations of the alpha-(1-->6) linkage and the primary hydroxyl groups were significantly improved and in excellent agreement with homo- and heteronuclear coupling constants. The difference between the two classes of force field (more structured and less structured carbohydrate-water interaction) was underlined by calculation of the isotropic hydration as calculated by radial pair distributions. At one extreme, the radial O em leader O pair distribution function yielded a peak density of 2.3 times the bulk density in the first hydration shell when using the older CHARMM force field, whereas the maximum density observed in the GLYCAM force field was calculated to be 1.0, at the other extreme.

Algorithms↗
PubMed2002

New insights into the allosteric mechanism of human hemoglobin from molecular dynamics simulations.

It is still difficult to obtain a precise structural description of the transition between the deoxy T-state and oxy R-state conformations of human hemoglobin, despite a large number of experimental studies. We used molecular dynamics with the Path Exploration with Distance Constraints (PEDC) method to provide new insights into the allosteric mechanism at the atomic level, by simulating the T-to-R transition. The T-state molecule in the absence of ligands was seen to have a natural propensity for dimer rotation, which nevertheless would be hampered by steric hindrance in the "joint" region. The binding of a ligand to the alpha subunit would prevent such hindrance due to the coupling between this region and the alpha proximal histidine, and thus facilitate completion of the dimer rotation. Near the end of this quaternary transition, the "switch" region adopts the R conformation, resulting in a shift of the beta proximal histidine. This leads to a sliding of the beta-heme, the effect of which is to open the beta-heme's distal side, increasing the accessibility of the Fe atom and thereby the affinity of the protein. Our simulations are globally consistent with the Perutz strereochemical mechanism.

Binding Sites↗
PubMed2001

Icosahedron-fcc transition size by molecular dynamics simulation of Lennard-Jones clusters at a finite temperature.

We studied finite-temperature ensembles of solid clusters produced by cooling liquid droplets either by evaporation or by a thermostat through a molecular dynamics calculation using the Lennard-Jones potential. The ensembles consist of either single or binary component clusters with 25% of the atoms 8% smaller in diameter than the other 75%. These clusters (380 clusters in total) exhibit various structures in the size range of n=160-2200, where n is the number of atoms in a cluster. For increasing size, the clusters show a gradual transition from icosahedral to a variety of structures: decahedral, face centered cubic, a small amount of hexagonal, and some icosahedral structures. They are asymmetrical or faulted. Electron diffraction patterns calculated with average structure factors of clusters after grouping them into several size regions are very similar to those experimentally observed. The size transition is around n=450 for single component clusters whatever the cooling process, evaporation or thermostat. This size is smaller than the experimental transition size estimated for argon clusters formed in a supersonic expansion. The transition size for binary component clusters is around n=600 for evaporative cooling, and larger for thermostatic cooling. The larger transition size found for the binary component clusters is consistent with the large icosahedral Au-Fe and Au-Cu alloy clusters observed experimentally.

Journal Article↗
PubMed1989

Molecular dynamics simulation of a phospholipid micelle.

The dynamic character of phospholipid aggregates limits conventional structural studies to the determination of average molecular features. In order to develop more detailed descriptions of phospholipid structure for comparison with experiment, the molecular dynamics of a hydrated lysophosphatidylethanolamine (LPE) micelle, incorporating 85 LPE and 1591 water molecules, have been simulated. Comparison of the initial and equilibrated micelles shows substantial differences both in LPE hydrocarbon chain conformation and polar head-group-solvent interactions. Although these changes produce only subtle effects on the averaged structural properties of the system, the alterations in hydrocarbon chain packing and head-group solvation appear to mimic a polymorphic pretransition from a spherical toward a cylindrical micelle structure.

Colloids↗
PubMed2005

Ab initio molecular dynamics simulation of the aqueous Ru2+/Ru3+ redox reaction: the Marcus perspective.

A well-behaved (low spin) transition metal aqua ion, Ru(aq)(2+), is used as a model system in an ab initio molecular dynamics study of a redox half reaction to which the Marcus theory of electron transfer is assumed to apply. Using constraint methods, we show that aqueous Ru(2+) can be reversibly transformed to Ru(3+) under the control of the classical solvent electrostatic potential as order parameter. The mean force is found to vary linearly with the order parameter in accordance with the Marcus theory. As can be expected for a half reaction, the slope in the oxidized and reduced states are asymmetric differing by approximately a factor of two. As a further test, we verify that the corresponding quadratic potential of mean force is in excellent agreement with the free energy profile obtained from the Gaussian distribution of potential fluctuations sampled from free (unconstrained) runs of the reduced and oxidized system. Similar to experimental electrochemical methods, our simulation scheme enables us to manipulate the effective thermodynamic driving force and align the free energy minima of product and reactant state. The activation energy and reaction entropy computed under these conditions are discussed and analyzed from the Marcus perspective.

Journal Article↗
PubMed1995

Homology modeling and molecular dynamics simulation of human prothrombin fragment 1.

The crystallographic structure of bovine prothrombin fragment 1 bound with calcium ions was used to construct the corresponding human prothrombin structure (hf1/Ca). The model structure was refined by molecular dynamics to estimate the average solution structure. Accommodation of long-range ionic forces was essential to reach a stable solution structure. The gamma-carboxyglutamic acid (Gla) domain and the kringle domain of hf1/Ca independently equilibrated. Likewise, the hydrogen bond network and the calcium ion coordinations were well preserved. A discussion of the phospholipid binding of the vitamin K-dependent coagulation proteins in the context of the structure and mutational data of the Gla domain is presented.

1-Carboxyglutamic Acid↗
PubMed1999

Analysis of affinities of penicillins for a class C beta-lactamase by molecular dynamics simulations.

We present a calculation for the binding free energy difference between two complexes of the class C beta-lactamase from Enterobacter cloacae with foramidocillin (FOPC) and with piperacillin (PIPC). The calculation was carried out by means of the thermodynamic integration (TI) method implemented with molecular dynamics (MD). By use of the available crystal structure of the class C beta-lactamase from E. cloacae, the structures of the beta-lactamase-FOPC (FOPC complex) and beta-lactamase-PIPC (PIPC complex) complexes were built by molecular modeling and equilibrated with MD simulations. FOPC were gradually converted into PIPC in both the solution and the enzyme system by means of MD/TI methods during the MD simulation. The structure of the PIPC complex as derived by the MD/TI simulation was similar to that of the PIPC complex obtained from molecular modeling. The calculated difference in the free energy of binding (deltadeltaGbind) was -2.2 kcal/mol. This compares well with the experimental value of -1.5 kcal/mol. The results indicate that the binding affinity of FOPC is lower than that of PIPC because of the greater difficulty of desolvation for FOPC upon binding to the enzyme. This calculation suggests that the desolvation of the ligand, as well as its interaction with the beta-lactamase, is important in understanding the relative affinity of the ligands with beta-lactamase.

Crystallography↗
PubMed1998

Molecular dynamics simulations of individual alpha-helices of bacteriorhodopsin in dimyristoylphosphatidylcholine. II. Interaction energy analysis.

The concepts of hydrophobicity and hydrophobic moments have been applied in attempts to predict membrane protein secondary and tertiary structure. The current paper uses molecular dynamics computer calculations of individual bacteriorhodopsin helices in explicit dimyristoylphosphatidylcholine bilayers to examine the atomic basis of these approaches. The results suggest that the types of interactions between a particular amino acid and the surrounding bilayer depend on the position and type of the amino acid. In particular, aromatic residues are seen to interact favorably at the interface region. Analysis of the trajectories in terms of hydrophobic moments suggests the presence of a particular face that prefers lipid. The results of these simulations may be used to improve secondary structure prediction methods and to provide further insights into the two-stage model of protein folding.

Amino Acids↗
PubMed2001

Computer modeling and molecular dynamics simulations of ligand bound complexes of bovine angiogenin: dinucleotide topology at the active site of RNase a family proteins.

We have undertaken the modeling of substrate-bound structures of angiogenin. In our recent study, we modeled the dinucleotide ligand binding to human angiogenin. In the present study, the substrates CpG, UpG, and CpA were docked onto bovine angiogenin. This was achieved by overcoming the problem of an obstruction to the B1 site by the C-terminus and identifying residues that bind to the second base. The modeled complexes retain biochemically important interactions. The docked models were subjected to 1 ns of molecular dynamics, and structures from the simulation were refined by using simulated annealing. Our models explained the enzyme's specificity for both B1 and B2 bases as observed experimentally. The nature of binding of the dinucleotide substrate was compared with that of the mononucleotide product. The models of these complexes were also compared with those obtained earlier with human angiogenin. On the basis of the simulations and annealed structures, we came up with a consensus topology of dinucleotide ligands that binds to human and bovine angiogenins. This dinucleotide conformation can serve as a starting model for ligand-bound complex structures for RNase A family of proteins. We demonstrated this capability by generating the complex structure of CpA bound to eosinophil-derived neurotoxin (EDN) by fitting the consensus topology of CpA to the crystal structure of native EDN.

Animals↗
PubMed1996

TRAJAN: a tool for analyzing trajectories from molecular simulations.

Molecular dynamics simulations of biological systems are notoriously difficult to analyze because of the complexity of the information that contain. We describe a new method for analyzing trajectories from simulations in order to extract important features of the motion. The trajectory of each atom is partitioned into conformation wells, in each of which its motion is assumed to be predominantly harmonic oscillation around an average position. Thus each atom moves anharmonically through a sequence of wells during the trajectory. The movement of atoms between wells, their ellipsoids of motion within each well, and correlations in the motion of atoms are quantified and can be visualized with molecular graphics. The TRAJAN analysis procedure is applicable to trajectories from equilibrium and nonequilibrium simulations and is not restricted to molecular dynamics simulations. Its application is demonstrated for a range of model systems.

Algorithms↗
PubMed1991

Conformational analysis of a IgG1 hinge peptide derivative in solution determined by NMR spectroscopy and refined by restrained molecular dynamics simulations.

The hinge region links the antigen binding Fab part to the constant Fc domain in immunoglobulins. For the hinge peptide derivative [AcThr(OtBu)-Cys-Pro-Pro-Cys-Pro-Ala-ProNH2]2 the assignment of the 1H and 13C resonances was achieved by two-dimensional nmr techniques: total correlation spectroscopy (TOCSY), nuclear Overhauser enhancement spectroscopy (NOESY), rotating frame nuclear Overhauser enhancement spectroscopy (ROESY), heteronuclear multiple quantum coherence (HMQC) transfer, and a HSQC (modified Overbodenhausen experiment) with high resolution in F1, which was several times folded in F1 but still phase correctable. Conformational relevant parameters (78 nuclear Overhauser effect distance restraints, 3JHH for prochiral assignments, temperature gradients) were determined by nmr and served as input data for molecular dynamics (MD) structure refinement. A simulated model compound corresponding to the [Cys-Pro-Pro-Cys]2 core elongated by the peptide chains in the Fab and Fc direction served as a starting structure for the final MD run. The conformation calculated in in vacuo does not agree with the C2 symmetry required from nmr data, but the structure obtained by a water simulation fulfills the requirement. Here the core of the hinge peptide derivative adopts a polyproline II double helix as in the x-ray structure of IgG1. Hence, segments responsible for the internal flexibility are located outside the core as confirmed by the flexibility of the solvent exposed C termini.

Amino Acid Sequence↗
PubMed2001

Molecular dynamics simulations of a highly charged peptide from an SH3 domain: possible sequence-function relationship.

A seven-residue peptide that is highly conserved in SH3 domains despite being far from the active site has been shown by NMR to be stable in solution. This peptide, biologically important because it is a likely folding nucleus for SH3 domains, provides a challenging subject for molecular dynamics because it is highly charged. We present stable, 10-ns simulations of both the native-like diverging turn structure and a helical model. Free energies of these two conformations, estimated through MM-PBSA analysis using several force fields, suggest a comparable free energy (DeltaDeltaG < or =6 kcal/mol) for native and helix conformations. NOE intensities calculated from the native trajectory reproduce experimental data quite well, suggesting that the conformations sampled by the trajectory reasonably represent those observed in the NMR experiment. The molecular dynamics results, as well as sequence analysis of a diverse 690-member family of SH3 domain proteins, suggest that the presence of two elements is essential for formation of the diverging turn structure: a pair of residues with low helical propensity in the turn region and, as previously recognized, two hydrophobic residues to close the end of the diverging turn. Thus, these two sequence features may form the structural basis for the function of this peptide as a folding nucleus in this family of proteins.

Computer Simulation↗
PubMed2004

Molecular dynamics simulations of duplex stretching reveal the importance of entropy in determining the biomechanical properties of DNA.

Advances in nanomanipulation techniques have made it possible to measure the response of an individual biomolecule to a force applied in the laboratory. Experiments that stretch a single molecule of duplex DNA have been difficult to interpret theoretically, particularly as the major changes in molecular structure caused by the force cannot be measured. In principle, computer simulation can calculate these conformational changes in atomic level detail, but to date such studies have failed to reproduce the experimental data due to the computational expense of the calculations. Here we show that a combination of molecular modeling and statistical physics can be used successfully to understand the stretching behavior of DNA. Our simulations provide new information about the dynamics of DNA denaturation under force in atomic level detail and also show the importance of entropy in determining biomechanical properties in general.

Biomechanical Phenomena↗
PubMed2003

Molecular dynamics simulation of compression-induced solid-to-solid phase transitions in colloidal monolayers.

The compression of two-dimensional colloidal monolayers, consisting of polystyrene particles trapped at an oil-water interface and interacting via dipole-dipole potentials, is investigated by the molecular dynamics technique. In particular, the pair correlation function and global orientational order parameter of the monolayers are calculated as a function of the particle coverage. The simulation results exhibit a sequence of hexagonal-to-rhombohedral-to-hexagonal phase transitions of the monolayers under anisotropic compression. The influence of defects in the monolayers on the solid-to-solid phase transitions is also examined. The simulations show that the stability of the rhombohedral phase is relatively sensitive to lattice defects, while, under the same conditions, the hexagonal phase is very stable. Finally, the simulation results are compared with recent experimental observations, and the implications of the present computer simulations for diffusion mechanisms and protein folding studies are discussed briefly.

Journal Article↗
PubMed2003

Interpretation of small angle X-ray measurements guided by molecular dynamics simulations of lipid bilayers.

Reconstruction and interpretation of lipid bilayer structure from X-ray scattering often rely on assumptions regarding the molecular distributions across the bilayer. It is usually assumed that changes in head-head spacings across the bilayer, as measured from electron density profiles, equal the variations in hydrocarbon thicknesses. One can then determine the structure of a bilayer by comparison to the known structure of a lipid with the same headgroup. Here we examine this procedure using simulated electron density profiles for the benchmark lipids DMPC and DPPC. We compare simulation and experiment in both real and Fourier space to address two main aspects: (i) the measurement of head-head spacings from relative electron density profiles, and (ii) the determination of the absolute scale for these profiles. We find supporting evidence for the experimental procedure, thus explaining the robustness and consistency of experimental structural results derived from electron density profiles. However, we also expose potential pitfalls in the Fourier reconstruction that are due to the limited number of scattering peaks. Volumetric analysis of simulated bilayers allows us to propose an improved, yet simple method for scale determination. In this way we are able to remove some of the restrictions imposed by limited scattering data in constructing reliable electron density profiles.

1,2-Dipalmitoylphosphatidylcholine↗