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PubMed2004

Force-field parametrization and molecular dynamics simulations of Congo red.

Congo red, a diazo dye widely used in medical diagnosis, is known to form supramolecular systems in solution. Such a supramolecular system may interact with various proteins. In order to examine the nature of such complexes empirical force field parameters for the Congo red molecule were developed. The parametrization of bonding terms closely followed the methodology used in the development of the charmm22 force field, except for the calculation of charges. Point charges were calculated from a fit to a quantum mechanically derived electrostatic potential using the CHELP-BOW method. Obtained parameters were tested in a series of molecular dynamics simulations of both a single molecule and a micelle composed of Congo red molecules. It is shown that newly developed parameters define a stable minimum on the hypersurface of the potential energy and crystal and ab initio geometries and rotational barriers are well reproduced. Furthermore, rotations around C-N bonds are similar to torsional vibrations observed in crystals of diphenyl-diazene, which confirms that the flexibility of the molecule is correct. Comparison of results obtained from micelles molecular dynamics simulations with experimental data shows that the thermal dependence of micelle creation is well reproduced.

Biphenyl Compounds↗

PubMed2006

Molecular dynamics simulations of the effect of the composition of calcium alumino-silicate intergranular films on alumina grain growth.

Molecular dynamics simulations were performed to study the effect of the composition of the intergranular film (IGF) on anisotropic and isotropic grain growth in alpha-Al2O3. In the simulations, the IGF is formed while in contact with two differently oriented alumina crystals, with the alumina (0001) basal plane on one side and the (110) prism plane on the other. Five different compositions in the IGFs were studied. Results show preferential growth along the [110] of the (110) surface in comparison to growth along the [0001] direction on the (0001) surface for compositions near a Ca/Al ratio of 0.5. Such preferential growth is consistent with anisotropic grain growth in alumina, where platelets form because of faster growth of the prism orientations than the basal orientation. The simulations also show the mechanism by which Ca ions in the IGF inhibit growth on the basal surface. At compositions with high or low Ca/Al ratios, growth along each surface normal is equivalent, indicating isotropic grain growth, although the attachment rates are quite different, which may indicate differences between normal grain growth and abnormal, but isotropic, grain growth. The simulations provide an atomistic view of attachment onto crystal surfaces, affecting grain growth in alumina.

Journal Article↗

PubMed2006

Molecular dynamics simulation study of superhydrated perdeuterated natrolite using a new interaction potential model.

To test a new interaction potential, molecular dynamics simulations of zeolite natrolite were performed for the structures under ambient conditions hydrated by perdeuterated water and at high pressure (1.87 GPa) in the superhydrated phase, which were recently studied by neutron diffraction. The experimental structures were reproduced with reasonable accuracy, and the hydrogen bond features are discussed. As in ordinary natrolite, a flip motion of water molecules around the HOH bisector is found, which, together with translational oscillations, gives rise to transient hydrogen bonds between water molecules, which do not appear from experimental equilibrium coordinates. The dynamics of water molecules can explain some problems encountered in refining the experimental structure. Vibrational spectra of natrolite containing perdeuterated water, which are not yet measured, were simulated, and their qualitative trend is discussed.

Journal Article↗

PubMed2004

Molecular-dynamics simulation of the effect of ions on a liquid-liquid interface for a partially miscible mixture.

Molecular-dynamics simulations were performed to model the effect of added salt ions on the liquid-liquid interface in a partially miscible system. Simulations of the interface between saturated phases of a model 1-hexanol+water system show a bilayer structure of 1-hexanol molecules at the interface with -OH heads of the first layer directed into the water phase and the opposite orientation for the second layer. The alignment of the polar -OH groups at the interface stabilizes a charge separation of sodium and chloride ions when salt is introduced into the aqueous phase, producing an electrical double layer. Chloride ions aggregate nearer the interface and sodium ions move toward the bulk water phase, consistent with the explanation that the -OH alignment presents a region of partial positive charges to which the hydrated chloride atoms are attracted. Ions near the interface were found to be less solvated than those in the bulk phase. An electric field was also applied to drive ions through the interface. Ions crossing the interface tended to shed water molecules as they entered the hexanol bilayer, leaving a trail of water molecules. Stabilization and facilitated transport of the ion by interactions with the second layer of hexanol molecules appeared to be an important step in the mechanism of sodium ion transport.

Journal Article↗

PubMed2004

Density inhomogeneity and diffusion behavior of fluids in micropores by molecular-dynamics simulation.

The density profiles and the diffusion behavior of fluid argon confined in micropores were studied by molecular-dynamics simulations. The effects of pore size (width), temperature and number density on the density profiles and the self-diffusion coefficients in micropores were simulated with pore widths from 0.6 to 4.0 nm. The density profiles are greatly affected by the pore size. Strong inhomogeneities in the channel direction and vapor-liquid phase separation in the micropores were observed when initial conditions were chosen in the coexistence region of the fluid. The self-diffusion coefficient in the channel direction in the pores was found to be much lower than in the bulk, and decreasing with decreasing pore size, decreasing temperature, and increasing density.

Journal Article↗

PubMed2006

Rheological and structural studies of linear polyethylene melts under planar elongational flow using nonequilibrium molecular dynamics simulations.

We present various rheological and structural properties of three polyethylene liquids, C50H102, C78H158, and C128H258, using nonequilibrium molecular dynamics simulations of planar elongational flow. All three melts display tension-thinning behavior of both elongational viscosities, eta1 and eta2. This tension thinning appears to follow the power law with respect to the elongation rate, i.e., eta approximately epsilon(b), where the exponent b is shown to be approximately -0.4 for eta1 and eta2. More specifically, b of eta1 is shown to be slightly larger than that of eta2 and to increase in magnitude with the chain length, while b of eta2 appeared to be independent of the chain length. We also investigated separately the contribution of each mode to the two elongational viscosities. For all three liquids, the intermolecular Lennard-Jones (LJ), intramolecular LJ, and bond-stretching modes make positive contributions to both eta1 and eta2, while the bond-torsional and bond-bending modes make negative contributions to both eta1 and eta2. The contribution of each of the five modes decreases in magnitude with increasing elongation rate. The hydrostatic pressure shows a clear minimum at a certain elongation rate for each liquid, and the elongation rate at which the minimum occurs appears to increase with the chain length. The behavior of the hydrostatic pressure with respect to the elongation rate is shown to correlate with the intermolecular LJ energy from a microscopic viewpoint. On the other hand, R(ete)2 and R(g)2 appear to be correlated with the intramolecular LJ energy. The study of the effect of the elongational field on the conformation tensor c shows that the degree of increase of tr(c)-3 with the elongation rate becomes stronger as the chain length increases. Also, the well-known linear reaction between sigma and c does not seem to be satisfactory. It seems that a simple relation between sigma and c would not be valid, in general, for arbitrary flows.

Journal Article↗

PubMed2004

Nucleation and growth in pressure-induced phase transitions from molecular dynamics simulations: mechanism of the reconstructive transformation of NaCl to the CsCl-type structure.

We perform path sampling molecular dynamics on the pressure-induced reconstructive phase transition from NaCl to CsCl type structure. Unlike the molecular dynamics simulations prior to this work our approach does not drive the process by applying elevated pressure. As a consequence, we are able to observe nucleation events that initiate the successive transformation of the crystal. The competing phases are separated by an interface exhibiting a well-defined structure that propagates through the crystal during phase transition.

Journal Article↗

PubMed2000

Molecular dynamics simulation of metallothionein-drug complexes.

The intermolecular interactions of metallothionein with nitrogen mustard drugs were studied by molecular dynamics simulations. Previous laboratory experiments have defined selective alkylation of two cysteine residues, and selective binding was proposed to precede alkylation. The present study provides information about accessibility to cysteines based on evaluating the intermolecular energies and distances in the first few ps of dynamics simulations. A series of dynamics simulations was performed with three drug molecules positioned at the eight most solvent accessible cysteine residues of the dimeric form of the protein. Sites proximal to the sulfhydryl groups of Cys-33 and Cys-48 were found to be the most favorable for complexing the aziridinium forms of chlorambucil, melphalan, and mechlorethamine. The sites for preferential binding are in qualitative agreement with the sites of selective alkylation defined experimentally.

Binding Sites↗

PubMed2005

Molecular-dynamics simulations of dimethylsulfoxide-methanol mixtures.

We present molecular-dynamics (MD) computer simulation results for the local structures, hydrogen (H)-bond distribution, and dynamical properties of methanol (MeOH) and dimethylsulfoxide (DMSO) binary mixtures at ambient conditions over the entire composition range. The simulated heat of mixing and site-site pair distribution functions suggest that the intermolecular structures of the pure liquids are not markedly altered upon mixing. Nevertheless, H-bonding statistics show that aggregates of the type 1DMSO:1MeOH are formed and represent the predominant form of molecular association in these mixtures. Only a small fraction (10%) of DMSO molecules in MeOH-rich mixtures (85% in mole) forms H-bonding trimers of type 1DMSO:2MeOH. No evidence of other types of interspecies association is found. The self-diffusion coefficient for DMSO (MeOH) increases (decreases) upon mixing. The characteristic reorientation time tau1 of both species increases in the mixture, but the composition dependence is weak. The frequency spectrum of MeOH reorientational time-correlation function shows significant redshifts of the principal librational band as DMSO is added to the system, whereas the librational band of DMSO shows small alterations upon mixing. Our results are discussed in the light of previous simulation analyses for a similar system, DMSO-water mixtures, and compared with available experimental results.

Journal Article↗

PubMed2006

Molecular dynamics simulations of electron-alkali cation pairs in bulk water.

The structural, dynamic, and thermodynamic properties of an excess electron interacting with an alkali cation (Na+, K+, Li+) in bulk water were investigated by means of a mixed quantum-classical molecular dynamics simulation technique. This study includes a reparametrization of the electron-cation pseudopotentials. The free energy calculations for all three systems show that a contact electron-cation pair can be observed, which is either as stable as the dissociated pair (Li+) or more stable by only a few kT (Na+, K+). Given that the dissociation barrier is also quite small, we suggest that the average cation-electron distance in the experiments at room temperature will not depend on this free energy profile but rather on the minimization of the Coulombic repulsive interaction between like charges in the solvent medium. This enables us to compare the present molecular dynamics simulations with the spectroscopic data obtained for different ionic strengths. The overall trend of the UV-vis hydrated absorption spectra, namely, the shift toward shorter wavelengths at high ionic strengths, is fairly well reproduced. This confirms our hypothesis of statistical distribution of the cations and solvated electrons.

Cations↗

PubMed1993

Persistence analysis of the static and dynamical helix deformations of DNA oligonucleotides: application to the crystal structure and molecular dynamics simulation of d(CGCGAATTCGCG)2.

A theory and graphical presentation for the analysis of helix structure and deformations in oligonucleotides is presented. The parameters "persistence" and "flexibility" as defined in the configurational statistics of polymers of infinite length are reformulated at the oligonucleotide level in an extension of J. A. Schellman's method [(1974) Biopolymers, Vol. 17, pp. 217-226], and used as a basis for a systematic "Persistence Analysis" of the helix deformation properties for all possible subsequences in the structure. The basis for the analysis is a set of link vectors referenced to individual base pairs, and is limited to sequences exhibiting only perturbed rod-like behavior, i.e., below the threshold for supercoiling. The present application of the method is concerned with a physical model for the angular component of bending, so the link vectors are defined as the unit components of a global helix axis obtained by the procedure "Curves" of R. Lavery and H. Sklenar [(1988) J. Biomol. Struct. Dynam., Vol. 6, pp. 63-91; (1989) ibid., Vol. 6, pp. 655-667]. A discussion of the relationship between global bending and relative orientation of base pairs is provided. Our approach is illustrated by analysis of some model oligonucleotide structures with intrinsic kinks, the crystal structure of the dodecamer d(CGCGAATTCGCG)2, and the results of two molecular dynamics simulations on this dodecamer using two variations of the GROMOS force field. The results indicate that essentially all aspects of curvature in short oligonucleotides can be determined, such as the position and orientation of each bend, the sharpness or smoothness, and the location and linearity of subsequences. In the case of molecular dynamics simulations, where a Boltzmann ensemble of structures is analyzed, the spatial extent of the deformations (flexibility) is also considered.

Base Sequence↗

PubMed2001

Molecular dynamics simulations of wild-type and point mutation human prion protein at normal and elevated temperature.

This paper describes molecular dynamics simulations of prion protein at 300 and 500 K. This was undertaken to gain insight into the factors involved in the stability of prion protein. Simulations were done using the Particle Mesh Ewald (PME) method using a homology model of the C-terminal fragment of human prion protein and the NMR structure of the human prion protein. The simulations at both 300 and 500 K were stable. Simulations were also undertaken with a mutant known to be associated with prion disease: Asp178Asn. The Asp178Asn simulation trajectory was observed to be much less stable than for the wild-type protein trajectory. Significant breakdown in secondary structure was observed for Asp178Asn at 500 K.

Computer Simulation↗

PubMed2005

Molecular dynamics simulation of the M2 helices within the nicotinic acetylcholine receptor transmembrane domain: structure and collective motions.

Multiple nanosecond duration molecular dynamics simulations were performed on the transmembrane region of the Torpedo nicotinic acetylcholine receptor embedded within a bilayer mimetic octane slab. The M2 helices and M2-M3 loop regions were free to move, whereas the outer (M1, M3, M4) helix bundle was backbone restrained. The M2 helices largely retain their hydrogen-bonding pattern throughout the simulation, with some distortions in the helical end and loop regions. All of the M2 helices exhibit bending motions, with the hinge point in the vicinity of the central hydrophobic gate region (corresponding to residues alphaL251 and alphaV255). The bending motions of the M2 helices lead to a degree of dynamic narrowing of the pore in the region of the proposed hydrophobic gate. Calculations of Born energy profiles for various structures along the simulation trajectory suggest that the conformations of the M2 bundle sampled correspond to a closed conformation of the channel. Principal components analyses of each of the M2 helices, and of the five-helix M2 bundle, reveal concerted motions that may be relevant to channel function. Normal mode analyses using the anisotropic network model reveal collective motions similar to those identified by principal components analyses.

Amino Acid Sequence↗

PubMed2003

Molecular dynamics simulations to determine the optimal loop length in the helix-loop-helix motif.

In this study, 100 ps molecular dynamics simulations were conducted to determine the optimal length of the Gly loop in the helix-loop-helix motif. The results revealed that the length of the loop significantly affected the stability of the two alpha-helices. In addition, the optimal loop length to maintain the highest helicity of the target peptide was found to be the one corresponding to 7 Gly residues. Longer loop length resulted in structural destabilization due to the entropic effect, while shorter loop length was not suitable to achieve intrachain packing of the two alpha-helices.

Amino Acid Sequence↗

PubMed2006

Characterization of a catalytic ligand bridging metal ions in phosphodiesterases 4 and 5 by molecular dynamics simulations and hybrid quantum mechanical/molecular mechanical calculations.

Cyclic nucleotide phosphodiesterases (PDEs) constitute a large superfamily of enzymes regulating concentrations of intracellular second messengers cAMP and cGMP through PDE-catalyzed hydrolysis. Although three-dimensional x-ray crystal structures of PDE4 and PDE5 have been reported, it is uncertain whether a critical, second bridging ligand (BL2) in the active site is H2O or HO- because hydrogen atoms cannot be determined by x-ray diffraction. The identity of BL2 is theoretically determined by performing molecular dynamics simulations and hybrid quantum mechanical/molecular mechanical (QM/MM) calculations, for the first time, on the protein structures resolved by x-ray diffraction. The computational results confirm our previous suggestion, which was based on QM calculations on a simplified active site model, that BL2 in PDE4 should be HO-, rather than H2O, serving as the nucleophile to initialize the catalytic hydrolysis of cAMP. The molecular dynamics simulations and QM/MM calculations on PDE5 demonstrate for the first time that the BL2 in PDE5 should also be HO- rather than H2O as proposed in recently published reports on the x-ray crystal structures, which serves as the nucleophile to initialize the PDE5-catalyzed hydrolysis of cGMP. These fundamental structural insights provide a rational basis for future structure-based drug design targeting PDEs.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1995

Application of two-dimensional NMR spectroscopy and molecular dynamics simulations to the conformational analysis of oligosaccharides corresponding to the cell-wall polysaccharide of Streptococcus group A.

This paper describes the use of a protocol for conformational analysis of oligosaccharide structures related to the cell-wall polysaccharide of Streptococcus group A. The polysaccharide features a branched structure with an L-rhamnopyranose (Rhap) backbone consisting of alternating alpha-(1-->2) and alpha-(1-->3) links and D-N-acetylglucosamine (GlcpNAc) residues beta-(1-->3)-connected to alternating rhamnose rings: [formula: see text] Oligomers consisting of three to six residues have been synthesized and nuclear magnetic resonance (NMR) assignments have been made. The protocol for conformational analysis of the solution structure of these oligosaccharides involves experimental and theoretical methods. Two-dimensional NMR spectroscopy methods (TOCSY, ROESY and NOESY) are utilized to obtain chemical shift data and proton-proton distances. These distances are used as constraints in 100 ps molecular dynamics simulations in water using QUANTA and CHARMm. In addition, the dynamics simulations are performed without constraints. ROE build-up curves are computed from the averaged structures of the molecular dynamics simulations using the CROSREL program and compared with the experimental curves. Thus, a refinement of the initial structure may be obtained. The alpha-(1-->2) and the beta-(1-->3) links are unambiguously defined by the observed ROE cross peaks between the A-B',A'-B and C-B,C'-B' residues, respectively. The branch-point of the trisaccharide CBA' is conformationally well-defined. Assignment of the conformation of the B-A linkage (alpha-(1-->3)) was problematic due to TOCSY relay, but could be solved by NOESY and T-ROESY techniques. A conformational model for the polysaccharide is proposed.

Carbohydrate Conformation↗

PubMed2006

Cannabinoid CB1 receptor recognition of endocannabinoids via the lipid bilayer: molecular dynamics simulations of CB1 transmembrane helix 6 and anandamide in a phospholipid bilayer.

The phospholipid bilayer plays a central role in the lifecycle of the endogenous cannabinoid, N-arachidonoylethanolamine (anandamide, AEA). Therefore, the orientation and location of AEA in the phospholipid bilayer with respect to key membrane associated proteins, is a central issue in understanding the mechanism of endocannabinoid signaling. In this paper, we report a test of the hypothesis that a betaXXbeta motif (formed by beta branching amino acids, V6.43 and I6.46) on the lipid face of the cannabinoid CB1 receptor in its inactive state may serve as an initial CB1 interaction site for AEA. Eight 6 ns NAMD2 molecular dynamics simulations of AEA were conducted in a model system composed of CB1 transmembrane helix 6 (TMH6) in a 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) bilayer. In addition, eight 6 ns NAMD2 molecular dynamics simulations of a low CB1 affinity (20:2, n-6) analog of AEA were conducted in the same model system. AEA was found to exhibit a higher incidence of V6.43/I6.46 groove insertion than did the (20:2, n-6) analog. In certain cases, AEA established a high energy of interaction with TMH6 by first associating with the V6.43/I6.46 groove and then molding itself to the lipid face of TMH6 to establish a hydrogen bonding interaction with the exposed backbone carbonyl of P6.50. Based upon these results, we propose that the formation of this hydrogen bonded AEA/TMH6 complex may be the initial step in CB1 recognition of AEA in the lipid bilayer.

Arachidonic Acids↗

PubMed1998

Molecular dynamic simulation of chaperonin-mediated protein folding.

We use molecular dynamics methods to simulate chaperonin-mediated refolding of barnase. A "chaperonin" term is added to the force field in order to simulate the hydrophobic environment in the central cavity of the chaperonins. Two aspects of our simulation results are consistent with experiments: (1) The hydrophobic environment of the central cavity of the chaperonin is an advantageous condition for the refolding of the misfolded intermediates. (2) One cycle of binding and release is not enough for the successful folding. Chaperonin-assisted protein folding maybe a procedure of multiple cycles of binding and release from the chaperonin.

Bacterial Proteins↗