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At least 1,801 records · Page 100Linked to original sources
PubMed2000

Sequence-dependent conformational perturbation in DNA duplexes containing an epsilonA.T mismatch using molecular dynamics simulation.

Previous experiments from this laboratory showed that 1, N:(6)-ethenoadenine (epsilonA) in 15mer DNA oligonucleotide duplexes with GGepsilonAGG and CCepsilonACC central sequences is repaired 3-5-fold more efficiently than in duplexes containing AAepsilonAAA and TTepsilonATT central sequences. This sequence dependence in repair rates appeared to correlate with the observed thermodynamic stability of these duplexes [Hang et al. (1998) J. Biol. Chem., 273, 33406-33413]. In the present work, unrestrained molecular dynamics was used to evaluate the sequence-dependent structural features of these duplexes. Explicit solvent and the particle mesh Ewald method were applied for the accurate representation of the electrostatic interactions. The differences observed in the axis- and intra-base pair parameters were primarily localized at the epsilonA*T mismatch in all sequences and indicate conformational diversity between the structures. However, all four structures remained in the B-conformational family. In the tip, tilt and propeller twist parameters for the five central base pairs, larger perturbations were found for the two duplexes with epsilonA flanked by A or T bases than for duplexes with epsilonA flanked by G or C bases. As a result of these perturbations, the average global curvature of the AAepsilonAAA and TTvarepsilonATT DNA duplexes was larger by approximately 12 degrees than that of the duplexes with the GGepsilonAGG and CCepsilonACC central sequences. The observed conformational differences between the duplexes containing A or T and G or C neighbors of epsilonA may contribute to the observed differential enzymatic repair of the same sequences.

Adenine↗
PubMed2004

Distinguish protein decoys by using a scoring function based on a new AMBER force field, short molecular dynamics simulations, and the generalized born solvent model.

Recent works have shown the ability of physics-based potentials (e.g., CHARMM and OPLS-AA) and energy minimization to differentiate the native protein structures from large ensemble of non-native structures. In this study, we extended previous work by other authors and developed an energy scoring function using a new set of AMBER parameters (also recently developed in our laboratory) in conjunction with molecular dynamics and the Generalized Born solvent model. We evaluated the performance of our new scoring function by examining its ability to distinguish between the native and decoy protein structures. Here we present a systematic comparison of our results with those obtained with use of other physics-based potentials by previous authors. A total of 7 decoy sets, 117 protein sequences, and more than 41,000 structures were evaluated. The results of our study showed that our new scoring function represents a significant improvement over previously published physics-based scoring functions.

Computational Biology↗
PubMed2006

Computational study of human phosphomannose isomerase: Insights from homology modeling and molecular dynamics simulation of enzyme bound substrate.

Phosphomannose isomerase is a zinc metalloenzyme that catalyzes the reversible isomerization of mannose-6-phosphate and fructose-6-phosphate, and the three-dimensional (3D) structure of human phosphomannose isomerase has not been reported. In order to understand the catalytic mechanism, the 3D structure of the protein is built by using homology modeling based on the known crystal structure of mannose-6-phosphate isomerase from (PDB code 1PMI). The model structure is further refined by energy minimization and molecular dynamics methods. The mannose-6-phosphate-enzyme complex is developed by molecular docking and the key residues involved in the ligand binding are determined, which will facilitate the understanding of the action mode of the ligands and guide further genetic studies. Our results suggest a hydride transfer mechanism of alpha-hydrogen between the C1 and C2 positions but do not support the cis-enediol mechanism. The detailed mechanism involves, on one side, Zn2+ mediating the movement of a proton between O1 and O2, and, on the other side, the hydrophobic environment formed in part by Tyr278 promoting transfer of a hydride ion.

Amino Acid Sequence↗
PubMed2005

Single-strand conformation polymorphism (SSCP) of oligodeoxyribonucleotides: an insight into solution structural dynamics of DNAs provided by gel electrophoresis and molecular dynamics simulations.

Studies on the solution structure dynamics of RNA/DNA are becoming crucially important. The phenomena of SSCP (single-strand conformation polymorphism), small RNA dynamics in a cell, and others can be related to the conformational changes of single-stranded (ss) RNAs/DNAs in solution. However, little is known about those dynamics. Only the intra-structural transition of ssDNAs in solution has been reported based on Watson-Crick (W-C) base-pairing. Here, we found a general feature of the SSCP phenomenon by studying the simpler molecules of ss-oligodeoxyribonucleotides. A single base substitution or a positional exchange of nucleotide in a highly homologous series of ss-dodecanucleotides led to a change in the mobility-in-gel. This was unexpected, since most of these nucleotides [such as d(A(11)G) or d(A(11)C)] have no possibility of forming W-C base-pairing. MD (molecular dynamics) experiments revealed differences in shape and size between the dynamic structures of these molecules which could affect their mobility-in-gel. In addition, a high correlation was observed between the electrophoretic mobility and the size-related parameters such as end-to-end distance obtained from MD simulations. Because the simulation was considerably shorter (nanosecond) than the experimental time-scale (second), the result must be considered conservatively; but it is nevertheless encouraging for utilizing MD simulation for structural analysis of oligonucleotides.

Base Sequence↗
PubMed2003

Molecular dynamics simulation of bacteriorhodopsin's photoisomerization using ab initio forces for the excited chromophore.

Retinal proteins are photoreceptors found in many living organisms. They possess a common chromophore, retinal, that upon absorption of light isomerizes and thereby triggers biological functions ranging from light energy conversion to phototaxis and vision. The photoisomerization of retinal is extremely fast, highly selective inside the protein matrix, and characterized through optimal sensitivity to incoming light. This article describes the first report of an ab initio quantum mechanical description of the in situ isomerization dynamics of retinal in bacteriorhodopsin, a microbial retinal protein that functions as a light-driven proton pump. The description combines ab initio multi-electronic state molecular dynamics of a truncated retinal chromophore model (N-methyl-gamma-methylpenta-2,4-dieniminium cation fragment) with molecular mechanics of the protein motion and unveils in complete detail the photoisomerization process. The results illustrate the essential role of the protein for the characteristic kinetics and high selectivity of the photoisomerization: the protein arrests inhomogeneous photoisomerization paths and funnels them into a single path that initiates the functional process. Supported by comparison with dynamic spectral modulations observed in femtosecond spectroscopy, the results identify the principal molecular motion during photoisomerization.

Bacteriorhodopsins↗
PubMed2005

Insights into the induced fit mechanism in antithrombin-heparin interaction using molecular dynamics simulations.

Heparin was isolated in the beginning of the 20th century and until today remains as one of the most important drugs able to interfere with the haemostatic process. Due to the side effects produced by heparin therapy, new promising drugs have been developed, as the synthetic pentasaccharide (synthetically derived from the sequence GlcN-GlcA-GlcN-IdoA-GlcN). The anticoagulant activity of this compound is based on potentiation of antithrombin (AT) inhibitory activity upon serine proteinases of clotting cascade, a mechanism based on the conformational modification of AT. In this context, we present here a molecular dynamics (MD) study of the interaction between the synthetic pentasaccharide and AT. The obtained data correctly predicted an induced fit mechanism in AT-pentasaccharide interaction, showing a solvent-exposed P1 residue instead of a hided conformation. Also, the specific contribution of important amino acid residues to the overall process was also characterized, both in (2)S(0) and (1)C(4) conformations of IdoA residue, suggesting that there is no conformational requirement to the interaction of this residue with AT. Altogether, the results show that MD simulations could be used to characterize and quantify the interaction of synthetic compounds with AT, predicting its specific capacity to induce conformational changes in AT structure. Thus, MD simulations of heparin (and heparin-derived)-AT interactions are proposed here as a powerful tool to assist and support drug design of new antithrombotic agents.

Allosteric Regulation↗
PubMed2001

Combined Monte Carlo and molecular dynamics simulation of hydrated lipid-cholesterol lipid bilayers at low cholesterol concentration.

We have applied a hybrid equilibration and sampling procedure for the atomic level simulation of a hydrated lipid bilayer to systems consisting of dipalmitoyl phosphatidylcholine (DPPC) and cholesterol, and palmitoyl-oleyl phosphatidylcholine (POPC) at low (approximately 6%) cholesterol concentration. The procedure is applied to bilayers of 94 molecules of DPPC, 6 molecules of cholesterol, and 3205 water molecules, and to bilayers of 120 molecules of POPC, 8 molecules of cholesterol, and 4268 water molecules, at a temperature of 325 K. After equilibration, three separate 400-ps continuous molecular dynamics runs, separated by 10,000 configurational bias Monte Carlo steps, were carried out for each system. Properties of the systems were calculated and averaged over the three separate runs. Results of the simulations are presented and compared with experimental data and with other recent simulations of DPPC and cholesterol, and of pure DPPC, and pure POPC. Certain properties of the bilayers are indistinguishable from cholesterol-free bilayers, including lateral diffusion and electron density. Other properties, most notably the order parameter profile, show the effect of cholesterol even at low concentrations.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2005

Molecular dynamics simulation of amphiphilic bistable [2]rotaxane langmuir monolayers at the air/water interface.

Bistable [2]rotaxanes display controllable switching properties in solution, on surfaces, and in devices. These phenomena are based on the electrochemically and electrically driven mechanical shuttling motion of the ring-shaped component, cyclobis(paraquat-p-phenylene) (CBPQT(4+)), between a monopyrrolotetrathiafulvalene (mpTTF) unit and a 1,5-dioxynaphthalene (DNP) unit located along a dumbbell component. The most stable state of the rotaxane (CBPQT(4+)@mpTTF) is that in which the CBPQT(4+) ring encircles the mpTTF unit, but a second less favored metastable co-conformation with the CBPQT(4+) ring surrounding the DNP (CBPQT(4+)@DNP) can be formed experimentally. For both co-conformations of an amphiphilic bistable [2]rotaxane, we report here the structure and surface pressure-area isotherm of a Langmuir monolayer (LM) on a water subphase as a function of the area per molecule. These results from atomistic molecular dynamics (MD) studies are validated by comparing with experiments based on similar amphiphilic rotaxanes. For both co-conformations, we found that as the area per molecule increases the thickness of the LM decreases while the molecular tilt increases. Both co-conformations led to similar LM thicknesses at the same packing area. From the simulated LM systems, we calculated the electron density profiles of the monolayer as a function of area per molecule, which show good agreement with experimental analyses from synchrotron X-ray reflectivity measurements of related systems. Decomposing the overall electron density profiles into component contributions, we found distinct differences in molecular packing in the film depending upon the co-conformation. Thus we find that the necessity of allowing the tetracationic ring to become solvated by water leads to differences in the structures for the two co-conformations in the LM. At the same packing area, the value of the overall tilt angle does not seem to be sensitive to whether the CBPQT(4+) ring is encircling the mpTTF or the DNP unit. However, the conformation of the dumbbell does depend on the location of the CBPQT(4+) ring, which is reflected in the segmental tilt angles of the mpTTF and DNP units. Using the Kirkwood-Buff formula in conjunction with MD calculations, we find the surface pressure-area isotherms for each co-conformation in which the CBPQT(4+)@mpTTF form has smaller surface tension and therefore larger surface pressure than the CBPQT(4+)@DNP at the same packing area, differences that decreases with increasing area per molecule, which is verified experimentally.

Air↗
PubMed2006

Vesicle shapes from molecular dynamics simulations.

Lipid bilayer membranes are known to form various structures such as large sheets or vesicles. When the two leaflets of the bilayer have an equal composition, the membrane preferentially forms a flat sheet or a spherical vesicle. However, a difference in the composition of the two leaflets may result in a curved bilayer or in a wide variety of vesicle shapes. Vesicles with different shapes have already been shown in experiments and diverse vesicle shapes have been predicted theoretically from energy minimization of continuous curves. Here we present a molecular dynamics study of the effect of small changes in the phospholipid headgroups on the spontaneous curvature of the bilayer and on the resulting vesicle shape transformations. Small asymmetries in the bilayers already result in high spontaneous curvature and large vesicle deformations. Vesicle shapes that are formed include ellipsoids, discoids, pear-shaped vesicles, cup-shaped vesicles, as well as budded vesicles. Comparison of these vesicles with theoretically derived vesicle shapes shows both resemblances and differences.

Algorithms↗
PubMed2006

Molecular dynamics simulations of liquid methanol and methanol-water mixtures with polarizable models.

A polarizable model for simulation of liquid methanol, compatible with the COS/G2 water model, has been developed using the Charge-on-Spring (COS) technique. The model consists of three point charges, with one polarizable center on the oxygen atom. The Lennard-Jones parameters on the oxygen atom together with the molecular polarizability were varied to reproduce the experimental heat of vaporization and density of liquid methanol at ambient conditions. We examined the energies of various methanol dimers in the gas phase and compared them with values obtained from ab initio calculations. The model was then used to study the thermodynamic, dynamic, structural, and dielectric properties of liquid methanol as well as of a methanol-water mixture. A microscopic picture of the structure of pure liquid methanol and of the methanol-water mixture is provided. Good agreement was found between the results from our model simulations and available experimental and ab initio calculation data. In particular, the experimental dielectric permittivity of 32 could be reproduced, which had been shown to be difficult when using nonpolarizable models.

Dimerization↗
PubMed2004

Molecular dynamics simulations of gas diffusion in metal-organic frameworks: argon in CuBTC.

The class of coordination polymers known as metal-organic frameworks (MOFs) has three-dimensional porous structures that are considered as a promising alternative to zeolites and other nanoporous materials for catalysis, gas adsorption, and gas separation applications. In this paper, we present the first study of gas diffusion inside an MOF and compare the observed diffusion to known behaviors in zeolites. Using grand canonical Monte Carlo and equilibrium molecular dynamics, we calculate the adsorption isotherm and self-, corrected, and transport diffusivities for argon in the CuBTC metal-organic framework. Our results indicate that diffusion of Ar in CuBTC is very similar to Ar diffusion in silica zeolites in magnitude, concentration, and temperature dependence. This conclusion appears to apply to a broad range of MOF structures.

Journal Article↗
PubMed2006

Molecular dynamics simulations applied to the study of subtypes of HIV-1 protease common to Brazil, Africa, and Asia.

Africa accounts for the majority of HIV-1 infections worldwide caused mainly by the A and C viral subtypes rather than B subtype, which prevails in the United States and Western Europe. In Brazil, B subtype is the major subtype, but F, C, and A also circulate. These non-B subtypes present polymorphisms, and some of them occur at sites that have been associated with drug resistance, including the HIV-1 protease (PR), one important drug target. Here, we report a Molecular Dynamics study of the B and non-B PR complexed with the inhibitor ritonavir to delineate the behavior of each subtype. We compare root mean squared deviation, binding free energy by linear interaction energy approach, hydrogen bonds, and intermolecular contact surface area between inhibitor and PR. From our results, we can provide a basis to understand the molecular mechanism of drug resistance in non-B subtypes. In this sense, we found a decrease of approx 4 kcal/mol in deltaG of binding between B and non-B subtypes. This corresponds to the loss of one hydrogen bond, which is in agreement with our H-bond analysis. Previous experimental affinity studies reported analogous results with inhibition constant values for non-B PR.

Africa↗
PubMedDate not supplied

Interactions of aryloxyphenoxypropionic acids with sensitive and resistant acetyl-coenzyme a carboxylase by homology modeling and molecular dynamic simulations.

Acetyl-coenzyme A carboxylase (ACCase) has been identified as one of the most important targets of herbicides. In the present study, we constructed homology models of the carboxyl-transferase (CT) domain of ACCase from sensitive and resistant foxtail and used these models as templates to study the molecular mechanism of herbicide resistance and stereochemistry-activity relationships of aryloxyphenoxypropionates (APPs). In the homology modeling structures, the dimer of the CT domain was formed by the side-to-side arrangement of the two monomers, in such a way that the N domain of one molecule is placed next to the C domain of the other. The dimeric association of sensitive foxtail CT was found to differ from that of resistant foxtail CT, and the spatial orientation of two key residues, Leu-695 and Ile-695, in these dimers also differed. The mutation of Ile to Leu may perturb the conformation of the dimeric interface, which may account for the molecular mechanism of herbicide resistance. Further docking analysis indicated that the binding model of high-active compounds is similar to that in the crystal structure of the enzyme-ligand complex. The different spatial orientations of ester groups of the isomers of APPs may explain the stereochemistry-activity relationship. Ser-698 formed a H-bonding interaction with all of the docked ligands, while Tyr-728 formed a pi-pi stacking interaction with some of the APPs. These findings may enhance our understanding of the molecular mechanism of herbicide resistance and stereochemistry-activity relationships, which may provide a new starting point for the identification of more potent inhibitors against both sensitive and resistant ACCase.

Acetyl-CoA Carboxylase↗

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