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PubMed1996

Simulated annealing with restrained molecular dynamics using a flexible restraint potential: theory and evaluation with simulated NMR constraints.

A new functional representation of NMR-derived distance constraints, the flexible restraint potential, has been implemented in the program CONGEN (Bruccoleri RE, Karplus M, 1987, Biopolymers 26:137-168) for molecular structure generation. In addition, flat-bottomed restraint potentials for representing dihedral angle and vicinal scalar coupling constraints have been introduced into CONGEN. An effective simulated annealing (SA) protocol that combines both weight annealing and temperature annealing is described. Calculations have been performed using ideal simulated NMR constraints, in order to evaluate the use of restrained molecular dynamics (MD) with these target functions as implemented in CONGEN. In this benchmark study, internuclear distance, dihedral angle, and vicinal coupling constant constraints were calculated from the energy-minimized X-ray crystal structure of the 46-amino acid polypeptide crambin (ICRN). Three-dimensional structures of crambin that satisfy these simulated NMR constraints were generated using restrained MD and SA. Polypeptide structures with extended backbone and side-chain conformations were used as starting conformations. Dynamical annealing calculations using extended starting conformations and assignments of initial velocities taken randomly from a Maxwellian distribution were found to adequately sample the conformational space consistent with the constraints. These calculations also show that loosened internuclear constraints can allow molecules to overcome local minima in the search for a global minimum with respect to both the NMR-derived constraints and conformational energy. This protocol and the modified version of the CONGEN program described here are shown to be reliable and robust, and are applicable generally for protein structure determination by dynamical simulated annealing using NMR data.

Computer Simulation↗
PubMed2002

A large scale molecular dynamics simulation code using the fast multipole algorithm (FMD): performance and application.

We present the performance of the fast classical molecular dynamics (MD) code, fast molecular dynamics (FMD), designed for efficient, object-oriented, and scalable large scale simulations, and summarize its application to a liquid crystalline cluster. FMD uses an implementation of the three-dimensional fast multipole method, developed in our group. The fast multipole method offers an efficient way (order O(N)) to handle long range electrostatic interactions, thus, enabling more realistic simulations of large molecular systems. Performance testing was carried out on IBM SP2, SGI Origin 2000, and CRAY T3E massively parallel systems using the MPI massage passing library. The electrostatic forces were tested on models of up to 100,000 randomly placed charges, and on protein and liquid crystalline molecular systems of over 99,000 atoms. Tests on the stability of the method are presented, along with comparisons with direct calculations, the NAMD2 code, and the physical multipole-based cell-multipole method.

Algorithms↗
PubMed2004

Sterically and guest-controlled self-assembly of calix[4]arene derivatives.

In solvents such as chloroform or benzene, tetraurea calix[4]arenes 1 form dimeric capsules in which one solvent molecule is usually included as guest. To explore the structural requirements for the formation of such hydrogen-bonded dimers we replaced one p-tolylurea residue by a simple acetamide function. The resulting calix[4]arene 2 a, substituted at its wide rim with one acetamide and three p-tolylurea functions, assumes a C(1)-symmetrical conformation in apolar solvents as shown by (1)H NMR, which is not compatible with the usual capsule. In the crystalline state, four molecules of 2 a, adopting a pinched cone conformation, assemble into a quasi S(4)-symmetrical tetramer stabilized by a cyclic array of 24 NH.O==C hydrogen bonds and four NH.pi interactions. Four acetamide groups are hydrogen-bonded to each other and pack tightly in the center of the assembly. All polar residues are buried inside the tetramer, the surface of which is lipophilic. Extensive NMR studies revealed similar structures in apolar solvents such as [D]chloroform or [D(6)]benzene for calixacetamides 2 a-c. The formation of these tetramers in solution is critically dependent on the size of the amide fragment, so that propionamide 2 d, butyramide 2 e, and p-tolylamide 2 f form only ill-defined aggregates. This is caused by steric crowding inside the tetrameric assembly. The tetramers persist during molecular dynamics simulations, and the optimized average structure of the MD run is similar to that found in the crystalline state. Theoretical studies revealed that cooperation of hydrogen bonds with multiple NH.pi, C--H.pi, and pi.pi attractions make the tetramer more stable than the capsular dimer with the solvent as guest. In the presence of tetraethylammonium salts, however, compounds 2 a-e form dimeric capsular assemblies, each incorporating a single ammonium cation. Only one of two possible regioisomeric dimers is formed, in which both acetamide groups are surrounded by two urea residues. These examples give striking evidence of how self-assembly in solution can be strongly dependent on subtle structural factors and of how the formation of dimeric capsules can be induced by the presence of an appropriate guest.

Journal Article↗
PubMed1999

The interactions of substituted pyrido[1,2-e]purines with oligonucleotides depend on the amphiphilic properties of their side chain.

Three pyrido[1,2-e]purines of increasing hydrophilicity have been synthesized to evaluate as anticancer agents. These drugs interact quite differently with a synthetic oligodeoxynucleotide d(CGATCG)2. [1] is very hydrophobic due to a phenyl residue in its side chain. It only shows limited interactions with the minihelix without any evidence of intercalation. [2] and [3], on the other hand, have one ([2]) or two ([3]) hydroxyl groups in their acyl chain and present rather amphiphilic properties. The result is a similar intercalation of these derivatives between C and G base pairs as revealed by intermolecular nOe, 1H and 31P chemical shift variations. Models for the intercalation of [2] are proposed using energy minimizations and molecular dynamics (MD) calculations subject to restraints from nOe connectivities. Simulations and experiments indicate weak stability and thus fast exchange of [2] in its intercalation site.

Animals↗
PubMed2005

Combining molecular dynamics with Lattice Boltzmann: a hybrid method for the simulation of (charged) colloidal systems.

We present a hybrid method for the simulation of colloidal systems that combines molecular dynamics (MD) with the Lattice Boltzmann (LB) scheme. The LB method is used as a model for the solvent in order to take into account the hydrodynamic mass and momentum transport through the solvent. The colloidal particles are propagated via MD and they are coupled to the LB fluid by viscous forces. With respect to the LB fluid, the colloids are represented by uniformly distributed points on a sphere. Each such point [with a velocity V(r) at any off-lattice position r] is interacting with the neighboring eight LB nodes by a frictional force F = xi0(V(r)-u(r)), with xi0 being a friction coefficient and u(r) being the velocity of the fluid at the position r. Thermal fluctuations are introduced in the framework of fluctuating hydrodynamics. This coupling scheme has been proposed recently for polymer systems by Ahlrichs and Dunweg [J. Chem. Phys. 111, 8225 (1999)]. We investigate several properties of a single colloidal particle in a LB fluid, namely, the effective Stokes friction and long-time tails in the autocorrelation functions for the translational and rotational velocity. Moreover, a charged colloidal system is considered consisting of a macroion, counterions, and coions that are coupled to a LB fluid. We study the behavior of the ions in a constant electric field. In particular, an estimate of the effective charge of the macroion is yielded from the number of counterions that move with the macroion in the direction of the electric field.

Journal Article↗
PubMed2006

Molecular dynamics study of the thermodynamic properties of calcium apatites. 2. Monoclinic phases.

Structural and thermodynamic properties of crystalline monoclinic calcium apatites, Ca10(PO4)6(X)2 (X=OH, Cl), were investigated for the first time using a molecular dynamics (MD) technique under a wide range of temperature and pressure conditions. The accuracy of the model at room temperature and atmospheric pressure was checked against crystal structural data, yielding maximum deviations of ca. 2%. The standard molar lattice enthalpy (DeltalatHo298) of the apatites was also calculated and compared with previously published experimental and MD results for the hexagonal polymorphs. High-temperature simulation runs were used to estimate the isobaric thermal expansivity coefficient and study the behavior of the crystal structure under heating. The heat capacity at constant pressure, Cp, in the range 298-1298 K, was estimated from the plot of the molar enthalpy of the crystal as a function of temperature, Hm=(Hm,298-298Cp,m)+Cp,mT, yielding Cp,m=635+/-7 J.mol-1.K-1 and Cp,m=608+/-14 J.mol-1.K-1 for hydroxy- and chlorapatite, respectively. High-pressure MD experiments, in the 0.5-75 kbar range, were performed to estimate the isothermal compressibility. The Parsafar-Mason equation of state was successfully used to fit the high-pressure p-Vm data, with an accuracy better than 0.03%.

Journal Article↗
PubMed1996

The STATIS method: characterization of conformational states of flexible molecules from molecular dynamics simulations in solution.

STATIS, a data analysis method used when data can be expressed as matrices, seems particularly well suited to characterize the internal molecular motions and conformational states extracted from MD trajectories. We first outline this method and the "adapted STATIS" method. Applications are presented for 18-crown-6 (simulated for 2 nsec in acetonitrile solution) and for the (L30)2Cu+ catenate (stimulated for 150 psec in chloroform). STATIS should be valuable for the classification of molecular conformations and simplified visualization of MD trajectories.

Acetonitriles↗
PubMed2003

Simulation of the different biological activities of diethylstilbestrol (DES) on estrogen receptor alpha and estrogen-related receptor gamma.

We describe the application of the molecular dynamics (MD) and molecular mechanics-generalized Born/surface area (MM-GB/SA) approaches to the simulation of the different biological activity of diethylstilbestrol (DES) on two highly homologous nuclear receptors-estrogen receptor alpha (ER-alpha) and estrogen-related receptor gamma (ERR-gamma). DES exerts an agonistic effect against ER-alpha and an antagonistic effect against ERR-gamma. Using the x-ray crystal structures of ER-alpha in the canonical agonist bound form (PDB code: 3ERD) and antagonist bound form (PDB code: 3ERT), ERR-gamma homology models have been constructed for the receptor in two different conformations. MM-GB/SA binding free energy calculations of DES in the ER-alpha and ERR-gamma structures suggest that DES exhibits a greater free energy of binding in the agonist bound conformation of ER-alpha, while the antagonist bound conformation is preferred for ERR-gamma. Further dissection of the free energy contributions coupled with calculation of the ligand binding pocket volume suggests that the van der Waals interactions for DES within the smaller binding pocket volume of ERR-gamma are less favorable and this is the main factor for DES antagonism in ERR-gamma. This approach has potential general applicability to the prediction of the biological activity of nuclear receptor ligands.

Amino Acid Sequence↗
PubMed2003

Effect of fiber optic probe geometry on depth-resolved fluorescence measurements from epithelial tissues: a Monte Carlo simulation.

Developing fiber optic probe geometries to selectively measure fluorescence spectra from different sublayers within human epithelial tissues will potentially improve the endogenous fluorescence contrast between neoplastic and nonneoplastic tissues. In this study, two basic fiber optic probe geometries, which are called the variable aperture (VA) and multidistance (MD) approaches, are compared for depth-resolved fluorescence measurements from human cervical epithelial tissues. The VA probe has completely overlapping illumination and collection areas with variable diameters, while the MD probe employs separate illumination and collection fibers with a fixed separation between them. Monte Carlo simulation results show that the total fluorescence detected is significantly higher for the VA probe geometry, while the probing depth is significantly greater for the MD probe geometry. An important observation is that the VA probe is more sensitive to the epithelial layer, while the MD probe is more sensitive to the stromal layer. The effect of other factors, including numerical aperture (NA) and tissue optical properties on the fluorescence measurements with VA and MD probe geometries, are also evaluated. The total fluorescence detected with both probe geometries significantly increases when the fiber NA is changed from 0.22 to 0.37. The sensitivity to different sublayers is found to be strongly dependent on the tissue optical properties. The simulation results are used to design a simple fiber optic probe that combines both the VA and MD geometries to enable fluorescence measurements from the different sublayers within human epithelial tissues.

Absorption↗
PubMed1991

Scanning electrochemical microscopy: theory and application of the transient (chronoamperometric) SECM response.

A study of the transient (chronoamperometric) response of the scanning electrochemical microscope (SECM) is presented. SECM transients were simulated digitally with a novel integrator based on a Krylov algorithm. The transients observed with planar electrodes (PE), microdisks (MD), and thin-layer cells (TLC) are shown to be limiting cases that fit the simulated SECM transients at very short, intermediate, and long times, respectively. A procedure is established that, provided the tip radius is known, allows the determination of the diffusion coefficient of the species in solution independent of its concentration and the number of electrons transferred in the electrode reaction. Experimental SECM transients are reported for the electrochemical oxidation of Fe(CN)6(4-) in KCl; the diffusion coefficient of Fe(CN)6(4-) was found to agree very well with the literature value.

Electrochemistry↗
PubMed2003

Comparing analysis methods for mutation-accumulation data: a simulation study.

We simulated single-generation data for a fitness trait in mutation-accumulation (MA) experiments, and we compared three methods of analysis. Bateman-Mukai (BM) and maximum likelihood (ML) need information on both the MA lines and control lines, while minimum distance (MD) can be applied with or without the control. Both MD and ML assume gamma-distributed mutational effects. ML estimates of the rate of deleterious mutation had larger mean square error (MSE) than MD or BM had due to large outliers. MD estimates obtained by ignoring the mean decline observed from comparison to a control are often better than those obtained using that information. When effects are simulated using the gamma distribution, reducing the precision with which the trait is assayed increases the probability of obtaining no ML or MD estimates but causes no appreciable increase of the MSE. When the residual errors for the means of the simulated lines are sampled from the empirical distribution in a MA experiment, instead of from a normal one, the MSEs of BM, ML, and MD are practically unaffected. When the simulated gamma distribution accounts for a high rate of mild deleterious mutation, BM detects only approximately 30% of the true deleterious mutation rate, while MD or ML detects substantially larger fractions. To test the robustness of the methods, we also added a high rate of common contaminant mutations with constant mild deleterious effect to a low rate of mutations with gamma-distributed deleterious effects and moderate average. In that case, BM detects roughly the same fraction as before, regardless of the precision of the assay, while ML fails to provide estimates. However, MD estimates are obtained by ignoring the control information, detecting approximately 70% of the total mutation rate when the mean of the lines is assayed with good precision, but only 15% for low-precision assays. Contaminant mutations with only tiny deleterious effects could not be detected with acceptable accuracy by any of the above methods.

Computer Simulation↗
PubMed2004

Brownian Dynamics, Molecular Dynamics, and Monte Carlo modeling of colloidal systems.

This paper serves as an introductory review of Brownian Dynamics (BD), Molecular Dynamics (MD), and Monte Carlo (MC) modeling techniques. These three simulation methods have proven to be exceptional investigative solutions for probing discrete molecular, ionic, and colloidal motions at their basic microscopic levels. The review offers a general study of the classical theories and algorithms that are foundational to Brownian Dynamics, Molecular Dynamics, and Monte Carlo simulations. Important topics of interest include fundamental theories that govern Brownian motion, the Langevin equation, the Verlet algorithm, and the Metropolis method. Brownian Dynamics demonstrates advantages over Molecular Dynamics as pertaining to the issue of time-scale separation. Monte Carlo methods exhibit strengths in terms of ease of implementation. Hybrid techniques that combine these methods and draw from these efficacies are also presented. With their rigorous microscopic approach, Brownian Dynamics, Molecular Dynamics, and Monte Carlo methods prove to be especially viable modeling methods for problems with challenging complexities such as high-level particle concentration and multiple particle interactions. These methods hold promising potential for effective modeling of transport in colloidal systems.

Journal Article↗
PubMed2005

Effect of a bound non-nucleoside RT inhibitor on the dynamics of wild-type and mutant HIV-1 reverse transcriptase.

HIV-1 reverse transcriptase (RT) is an important target for drugs used in the treatment of AIDS. Drugs known as non-nucleoside RT inhibitors (NNRTI) appear to alter the structural and dynamical properties of RT which in turn inhibit RT's ability to transcribe. Molecular dynamics (MD), principal component analysis (PCA), and binding free energy simulations are employed to explore the dynamics of RT and its interaction with the bound NNRTI nevirapine, for both wild-type and mutant (V106A, Y181C, Y188C) RT. These three mutations commonly arise in the presence of nevirapine and result in resistance to the drug. We show that a bound NNRTI hinders the motion of almost all RT amino acids. The mutations, located in the non-nucleoside RT inhibitor binding pocket, partially restore RT flexibility. The binding affinities calculated by molecular mechanics/Poisson-Boltzmann surface accessibility (MM-PBSA) show that nevirapine interacts stronger with wild-type RT than with mutant RT. The mutations cause a loss of van der Waals interactions between the drug and the binding pocket. The results from this study suggest that a good inhibitor should efficiently enter and maximally occupy the binding pocket, thereby interacting effectively with the amino acids around the binding pocket.

Amino Acid Substitution↗
PubMed2001

Modulation of intercalating properties of pyrido[1,2-e]purins via side-chain modifications: NMR and MD studies.

Two pyrido[1,2-e]purins with different side chain lengths have been synthesized to test their ability to intercalate inside DNA. The interactions of these drugs with synthetic oligodeoxy nucleotide d(CGATCG)2 have been studied with 1H and 31P NMR spectroscopy experiments. Molecule 1, rather amphiphilic (Log(P) = 1.3, due to its hydroxypropyl side chain) can intercalate GC sites of the mini helix, under a fast exchange mechanism and a 2:1 stoechiometry. The presence of a six methylen side chain in 2 (hydroxyhexyl side chain) is responsible for a relatively poor solubility of this molecule in water (log P = 2.3). Binding, rather than intercalation, of 2 to the external GC pairs is observed, severely limited by the formation of aggregates. Models for the intercalation of 1, are proposed using energy minimizations and Molecular Dynamics (MD) calculations subject to restraints from experimental nOe connectivities. Simulations and experiments both indicate fast exchange of 1 in its intercalation site.

DNA↗
PubMedDate not supplied

Diagnostic accuracy and reproducibility of tendency oriented perimetry in glaucoma.

PURPOSE: To evaluate the diagnostic capability of tendency oriented perimetry (TOP) in glaucoma. METHODS: A): The diagnostic accuracy of mean defect (MD), square-root of the loss variance (s LV), and number of pathologic points (NPP) was calculated in 295 normal and 414 glaucoma eyes (179 early, 112 moderate, and 123 advanced) examined with TOP. B): Threshold fluctuation (F) and its relationship with the loss variance (LV) was measured in 34 normal and 33 glaucoma eyes (mean MD=3 dB; SD=3.9) for TOP and for full-threshold perimetry (FT). C): Twenty-eight eyes with stable glaucoma (mean MD=9.5 dB; SD=7.2) were examined six times to quantify LV error. D): TOP and FT were tested with the simulation program PeriSim using different behavior models. RESULTS: A): The best diagnostic index in early glaucoma (MD<6dB) was sLV (specificity=90.2%, sensitivity=84.9). The three indices had similar precision in moderate and severe glaucoma. B): Threshold fluctuation and sLV were better correlated in TOP (r=0.72, p<0.01) than in FT (r=0.62, p<0.01). For normal subjects, in FT the incidence of F<2 dB was 8.82% and s LV<1.5 dB 5.88%. The same frequencies in TOP were 67.65% and 55.88%. C): Averaging six examinations reduced the sLV val ue by 22%. D): The threshold estimation error increased 1 dB in TOP in relation to FT for the same patient's behavior, but the error in TOP was lower than i n FT when the worst behavior was modeled. CONCLUSIONS: TOP is a good discriminator between glaucoma and normality. Perimetry results overestimate the real sLV value. TOP's high diagnostic ability is probably associated to the algorithm design and to less contaminating influences during the examination.

Adult↗
PubMed2005

Simulating the equation of state of model globular proteins adsorbed at a surface.

Monte Carlo computer simulation is used to follow the adsorption of a model globular and disordered protein at a hard surface and to simulate the surface equation of state for these molecules. The simulation utilizes the deformable globule model where the "protein" is treated as a collection of interacting subunits. Disordered globules are modeled as athermal molecules, whereas globular molecules have a strong attractive interaction between subunits. The surface equation of state is modeled by applying a known pressure to an adsorbed globule and following the changes in adsorbed conformation. Simulated equations of state for the disordered and globular molecules show features that are observed in experimental surface pressure versus area plots. In particular the simulated equations of state show "kinks" that correspond to regions where the adsorbed globules undergo conformational changes as they lift away from the surface in response to the increased pressure. The model proteins follow Bull's equation at low surface pressures in a way that is broadly in line with results from experiment, and the changes in conformation as a function of surface pressure are in line with predictions by DeFeijter and Benjamins made using a soft-particle model for adsorbed proteins.

Adsorption↗
PubMed2006

Towards the design of highly selective recognition sites into molecular imprinting polymers: a computational approach.

A computational approach to simulate the formation of possible imprinted polymers in acetonitrile solution for theophylline (THO) is proposed, using combined molecular dynamics (MD), molecular mechanics (MM), docking and site mapping computational techniques. Methacrylic acid (MAA) and methylmethacrylate (MMA) monomers are used to simulate possible homo and copolymer structures. The model is able predict binding affinity and selectivity when considering THO analogues, such as caffeine, theobromine, xanthine and 3-methylxanthine. Comparison with available experimental data is proposed.

Biosensing Techniques↗
PubMedDate not supplied

The spatial and energy dependence of bremsstrahlung production about beta point sources in H2O.

A Monte Carlo simulation was performed to characterize the spatial and energy distribution of bremsstrahlung radiation from beta point sources important to radioimmunotherapy (RIT). Using the EGS4 Monte Carlo code, the isotropic emission and transport of monoenergetic 0.1-, 0.5-, 1.0-, 2.0-, and 3.0-MeV electrons and 32P and 90Y beta particles was simulated in an infinite, homogeneous H2O phantom. The probability of bremsstrahlung production for each Monte Carlo-simulated electron step was accumulated in energy intervals not exceeding 5 keV and stored as a function of radial position. To validate this scheme, the EGS4 code was tested in the continuous slowing down approximation (csda) mode, with resulting radiation yields seen to agree with values in ICRU Report No. 37 (ICRU, Bethesda, MD, 1984) to better than 1.6%. The radiation yield calculated with the simulation of secondary particles is seen to be 3%-5% greater than the csda yield. The photon energy distributions are characterized by a typically broad bremsstrahlung spectrum with the probability of photon generation decreasing with radial distance. In the energy range 0.05-0.511 MeV, the probability for bremsstrahlung production from 90Y (2.76 x 10(-2) decay-1) is twice that from 32P (1.35 x 10(-2) decay-1). When passed through 10 cm of H2O and put upon a standard NaI scintillation camera, count rates of 2.3 x 10(-6) and 1.2 x 10(-6) counts s-1 Bq-1 are estimated from point sources of 90Y and 32P. These results predict the inherent spatial resolution limitation and provide the initial data required for modeling and analyzing the scatter, attenuation, and image formation processes in quantitative imaging of bremsstrahlung for RIT dosimetry.

Humans↗