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PubMed2006

Conformational transition pathway in the allosteric process of human glucokinase.

Glucokinase (GK) is an important enzyme for regulating blood glucose levels and a potentially attractive target for diabetes of the young type 2 and persistent hyperinsulinemic hypoglycemia of infancy. To characterize the conformational transition of GK from the closed state to the superopen state, a series of conventional molecular dynamics (MD) and target MD (TMD) simulations were performed on both the wild-type enzyme and its mutants. Two 10-ns conventional MD simulations showed that, although the allosteric site of GK is approximately 20 A away from the active site, the activator is able to enhance the activity of the enzyme through conformational restriction. Fourteen TMD simulations on GK and five of its mutants revealed a reliably conformational transition pathway. The overall conformational transition includes three stages, and three likely stable intermediate states were identified by free energy scanning for the snapshots throughout the pathway. The conformational transition feature revealed by our TMD simulations rationalized several important mutagenesis and kinetic data. Remarkably, the TMD simulations predicted that Y61S, I159A, A201R, V203E, and V452S mutations, which have not been investigated so far, may facilitate the opening process of GK. These predictions also have been verified by mutagenesis and kinetic analyses in this study. These observations are beneficial to understanding the mechanism of GK regulation and designing the compounds for treating metabolic diseases.

Allosteric Regulation↗
PubMed2003

Static and dynamic water molecules in Cu,Zn superoxide dismutase.

Understanding protein hydration is a crucial, and often underestimated issue, in unraveling protein function. Molecular dynamics (MD) computer simulation can provide a microscopic description of the water behavior. We have applied such a simulative approach to dimeric Photobacterium leiognathi Cu,Zn superoxide dismutase, comparing the water molecule sites determined using 1.0 ns MD simulation with those detected by X-ray crystallography. Of the water molecules detected by the two techniques, 20% fall at common sites. These are evenly distributed over the protein surface and located around crevices, which represent the preferred hydration sites. The water mean residence time, estimated by means of a survival probability function on a given protein hydration shell, is relatively short and increases for low accessibility sites constituted by polar atoms. Water molecules trapped in the dimeric protein intersubunit cavity, as identified in the crystal structure, display a trajectory mainly confined within the cavity. The simulation shows that these water molecules are characterized by relatively short residence times, because they continuously change from one site to another within the cavity, thus hinting at the absence of any relationship between spatial and temporal order for solvent molecules in proximity of protein surface.

Algorithms↗
PubMed1998

Identification of functional and unfolding motions of cutinase as obtained from molecular dynamics computer simulations.

The implementation of cutinase from Fusarium solani pisi as a fat-stain removing ingredient in laundry washing is hampered by its unfolding in the presence of anionic surfactants. In this work we present molecular dynamics (MD) computer simulations on cutinase and analysis procedures to distinguish the movements related to its functional behavior (e.g., substrate binding) from those related to the unfolding of the enzyme. Two kinds of MD-simulations were performed: a simulation mimicking the thermal motion at room temperature, and several simulations in which unfolding is induced either by high temperature or by using a modified water-protein interaction potential. Essential dynamics analyses (A. Amadei et al., Proteins 17:412-425, 1993) on the simulations identify distinct regions in the molecular structure of cutinase in which the motions occur for function and initial unfolding. The unfolding in various simulations starts in a similar way, suggesting that mutations in the regions involved might stabilize the enzyme without affecting its functionality.

Carboxylic Ester Hydrolases↗
PubMed2006

Lattice boltzmann versus molecular dynamics simulation of nanoscale hydrodynamic flows.

A fluid flow in a simple dense liquid, passing an obstacle in a two-dimensional thin film geometry, is simulated by molecular dynamics (MD) computer simulation and compared to results of lattice Boltzmann (LB) simulations. By the appropriate mapping of length and time units from LB to MD, the velocity field as obtained from MD is quantitatively reproduced by LB. The implications of this finding for prospective LB-MD multiscale applications are discussed.

Computer Simulation↗
PubMed1994

Solution conformation of a cyclic neurokinin antagonist: a NMR and molecular dynamics study.

The solution structure of a hexapeptide, cyclo (Gln-Trp-Phe-Gly-Leu-Met), which is a selective NK-2 antagonist, has been studied by a combination of two-dimensional nmr and molecular dynamics (MD) techniques. The simulation based on nmr and MD data resulted in the convergence to a family of structures. Free molecular dynamics for 50 ps in the presence of DMSO solvent molecules shows that the structure is energetically stable. One intramolecular hydrogen bond between the amide proton of Gln and the carbonyl oxygen of Gly was revealed. This result is consistent with the results from the measurement of the temperature coefficient of the amide protons. The extent of intermolecular hydrogen bonding between the amide protons of the peptide and DMSO was also revealed by the free MD simulation. The resulting structure of the cyclic peptide contains a variation type I' beta-turn in the Gly-Leu-Met-Gln segment. Comparison of the structure of this peptide with that of other NK-2 antagonist cyclic hexapeptides was made, and the activity of cyclic antagonists appears to be inversely related to the conformational rigidity of the cyclic peptides.

Amino Acid Sequence↗
PubMed2001

Characterization of NMR relaxation-active motions of a partially folded A-state analogue of ubiquitin.

The dominant dynamics of a partially folded A-state analogue of ubiquitin that give rise to NMR 15N spin relaxation have been investigated using molecular dynamics (MD) computer simulations and reorientational quasiharmonic analysis. Starting from the X-ray structure of native ubiquitin with a protonation state corresponding to a low pH, the A-state analogue was generated by a MD simulation of a total length of 33 ns in a 60%/40% methanol/water mixture using a variable temperature scheme to control and speed up the structural transformation. The N-terminal half of the A-state analogue consists of loosely coupled native-like secondary structural elements, while the C-terminal half is mostly irregular in structure. Analysis of dipolar N-H backbone correlation functions reveals reorientational amplitudes and time-scale distributions that are comparable to those observed experimentally. Thus, the trajectory provides a realistic picture of a partially folded protein that can be used for gaining a better understanding of the various types of reorientational motions that are manifested in spin-relaxation parameters of partially folded systems. For this purpose, a reorientational quasiharmonic reorientational analysis was performed on the final 5 ns of the trajectory of the A-state analogue, and for comparison on a 5 ns trajectory of native ubiquitin. The largest amplitude reorientational modes show a markedly distinct behavior for the two states. While for native ubiquitin, such motions have a more local character involving loops and the C-terminal end of the polypeptide chain, the A-state analogue shows highly collective motions in the nanosecond time-scale range corresponding to larger-scale movements between different segments. Changes in reorientational backbone entropy between the A-state analogue and the native state of ubiquitin, which were computed from the reorientational quasiharmonic analyses, are found to depend significantly on motional correlation effects.

Computer Simulation↗
PubMed1997

The sticking probability of a hydrogen atom on icy mantle.

In the present work, we investigate the sticking process of a hydrogen atom on the surface of dust grains. As a realistic model for the icy mantle of dust grains, we produced slab-shaped amorphous water ice with infinite area by classical molecular dynamics (MD) computational simulation using two-dimensional periodic boundary condition. The resulting amorphous water ice slabs at 10 K and 70 K were found to be in good agreement with the experimental high-density and low-density amorphous water ice, respectively. Then, we investigated the dynamical behaviors of an impinging H atom on the surface of it by MD simulations. The sticking probabilities of incident H atoms with several initial temperatures on 10 K and 70 K ice were obtained. It was found that most of H atoms colliding with the 10 K ice stuck on the surface of it. After having stuck, the impinging H atoms diffused on the surface of ice and became trapped in one of potential wells on the surface. The mobility of a H atom on the surface of the amorphous water ice was found to depend only upon the temperature of ice.

Computer Simulation↗
PubMed1994

5 nanosecond molecular dynamics and NMR study of conformational transitions in the sialyl-Lewis X antigen.

The range of internal motions of the sialyl Lewis-X (SLe(x)) tetrasaccharide (NeuNAc alpha 2-->3Gal beta 1-->4(Fuc alpha 1-->3)GlcNAc) [where Fuc is L-fucopyranose, Gal is D-galactopyranose, GlcNAc is 2-acetamido-2-deoxy-D-glucopyranose and NeuNAc is D-neuraminic acid (sialic acid)] was studied by restrained simulated annealing and restrained molecular dynamics (MD) calculations. Transitions between predominantly two conformational states were observed for the NeuNAc alpha (2-->3)Gal linkage, consistent with previous observations for this linkage in sialyl-N-acetyllactosamine. The MD trajectory was simulated for 5 ns of real time, in order to observe a statistically significant number of these relatively low-frequency transitions. The Fuc alpha(1-->3)GlcNAc and Gal beta (1-->4)GlcNAc linkages, however, showed more restricted flexibility within a single energy well (RMS differences for the time-averaged glycosidic torsion angles, and , were 50% lower than for the NeuNAc alpha(2-->3)Gal linkage), and approximate to a rigid conformation. NMR parameters [relative rotating-frame Overhauser enhancement (r.O.e.) and inter-glycosidic 3JCH] back-calculated from the MD simulation were in close agreement with experimentally measured values for the free reducing oligosaccharide in D2O solution.

Carbohydrate Conformation↗
PubMed2002

Long time dynamics of Met-enkephalin: comparison of explicit and implicit solvent models.

Met-enkephalin is one of the smallest opiate peptides. Yet, its dynamical structure and receptor docking mechanism are still not well understood. The conformational dynamics of this neuron peptide in liquid water are studied here by using all-atom molecular dynamics (MD) and implicit water Langevin dynamics (LD) simulations with AMBER potential functions and the three-site transferable intermolecular potential (TIP3P) model for water. To achieve the same simulation length in physical time, the full MD simulations require 200 times as much CPU time as the implicit water LD simulations. The solvent hydrophobicity and dielectric behavior are treated in the implicit solvent LD simulations by using a macroscopic solvation potential, a single dielectric constant, and atomic friction coefficients computed using the accessible surface area method with the TIP3P model water viscosity as determined here from MD simulations for pure TIP3P water. Both the local and the global dynamics obtained from the implicit solvent LD simulations agree very well with those from the explicit solvent MD simulations. The simulations provide insights into the conformational restrictions that are associated with the bioactivity of the opiate peptide dermorphin for the delta-receptor.

Biophysical Phenomena↗
PubMedDate not supplied

Development and validation of empirical force field parameters for netropsin.

The netropsin molecule preferentially binds to the four consecutive A.T base pairs of the DNA minor groove and could therefore inhibit the expression of specific genes. The understanding of its binding on a molecular level is indispensable for computer-aided design of new antitumor agents. This knowledge could be obtained via molecular dynamics (MD) and docking simulations, but in this case appropriate force field parameters for the netropsin molecule should be explicitly defined. Our parametrization was based on the results of quantum chemical calculations. The resulting set of parameters was able to reproduce bond lengths, bond angles, torsional angles of the ab initio minimized geometry within 0.03 A, 3 deg and 5 deg, respectively, and its vibrational frequencies with a relative error of 4.3% for low and 2.8% for high energy modes. To show the accuracy of the developed parameters we calculated an IR spectrum of the netropsin molecule using MD simulation and found it to be in good agreement with the experimental one. Finally, we performed a 10 ns long MD simulation of the netropsin-DNA complex immersed in explicit water. The overall complex conformation remained stable at all times, and its secondary structure was well retained.

Algorithms↗
PubMed2004

Molecular dynamics averaging of Xe chemical shifts in liquids.

The Xe nuclear magnetic resonance chemical shift differences that afford the discrimination between various biological environments are of current interest for biosensor applications and medical diagnostic purposes. In many such environments the Xe signal appears close to that in water. We calculate average Xe chemical shifts (relative to the free Xe atom) in solution in eleven liquids: water, isobutane, perfluoro-isobutane, n-butane, n-pentane, neopentane, perfluoroneopentane, n-hexane, n-octane, n-perfluorooctane, and perfluorooctyl bromide. The latter is a liquid used for intravenous Xe delivery. We calculate quantum mechanically the Xe shielding response in Xe-molecule van der Waals complexes, from which calculations we develop Xe (atomic site) interpolating functions that reproduce the ab initio Xe shielding response in the complex. By assuming additivity, these Xe-site shielding functions can be used to calculate the shielding for any configuration of such molecules around Xe. The averaging over configurations is done via molecular dynamics (MD). The simulations were carried out using a MD technique that one of us had developed previously for the simulation of Henry's constants of gases dissolved in liquids. It is based on separating a gaseous compartment in the MD system from the solvent using a semipermeable membrane that is permeable only to the gas molecules. We reproduce the experimental trends in the Xe chemical shifts in n-alkanes with increasing number of carbons and the large chemical shift difference between Xe in water and in perfluorooctyl bromide. We also reproduce the trend for a given solvent of decreasing Xe chemical shift with increasing temperature. We predict chemical shift differences between Xe in alkanes vs their perfluoro counterparts.

Journal Article↗
PubMed2006

A structure-based simulation approach for electron paramagnetic resonance spectra using molecular and stochastic dynamics simulations.

Electron paramagnetic resonance (EPR) spectroscopy using site-directed spin-labeling is an appropriate technique to analyze the structure and dynamics of flexible protein regions as well as protein-protein interactions under native conditions. The analysis of a set of protein mutants with consecutive spin-label positions leads to the identification of secondary and tertiary structure elements. In the first place, continuous-wave EPR spectra reflect the motional freedom of the spin-label specifically linked to a desired site within the protein. EPR spectra calculations based on molecular dynamics (MD) and stochastic dynamics simulations facilitate verification or refinement of predicted computer-aided models of local protein conformations. The presented spectra simulation algorithm implies a specialized in vacuo MD simulation at 600 K with additional restrictions to sample the entire accessible space of the bound spin-label without large temporal effort. It is shown that the distribution of spin-label orientations obtained from such MD simulations at 600 K agrees well with the extrapolated motion behavior during a long timescale MD at 300 K with explicit water. The following potential-dependent stochastic dynamics simulation combines the MD data about the site-specific orientation probabilities of the spin-label with a realistic rotational diffusion coefficient yielding a set of trajectories, each more than 700 ns long, essential to calculate the EPR spectrum. Analyses of a structural model of the loop between helices E and F of bacteriorhodopsin are illustrated to demonstrate the applicability and potentials of the reported simulation approach. Furthermore, effects on the motional freedom of bound spin-labels induced by solubilization of bacteriorhodopsin with Triton X-100 are examined.

Algorithms↗
PubMed1995

Structure and dynamics of a DNA.RNA hybrid duplex with a chiral phosphorothioate moiety: NMR and molecular dynamics with conventional and time-averaged restraints.

The three-dimensional structure of two thiophosphate-modified DNA.RNA hybrid duplexes d(GCTATAApsTGG).r(CCAUUAUAGC), one with R-thiophosphate chirality and one with S-thiophosphate chirality, have been determined by restrained molecular dynamics simulations (rMD). As the two yielded almost identical results, a description of results can be presented in the singular. The conformational flexibility of this hybrid has been investigated by employing time-averaged constraints during the molecular dynamics simulations (MD-tar). A set of structural restraints, comprising 322 precise interproton distance constraints obtained by a complete relaxation matrix analysis of the 2D NOE intensities as well as J coupling constants obtained from quantitative simulations of DQF-COSY cross-peaks in deoxyriboses, was reported in our previous paper [González, C., Stec, W., Kobylanska, A., Hogrefe, R. I., Reynolds, M., & James, T. L. (1994) Biochemistry 33, 11062-11072]. Multiple conformations of the deoxyribose moieties were evident from the scalar coupling constant analysis. Accurate distance constraints, obtained from complete relaxation matrix analysis, yielded a time-averaged solution structure via conventional restrained molecular dynamics which is not compatible with the experimental J coupling constants (root-mean-square deviation in J value approximately 2 Hz). However, vicinal coupling constant information can be reproduced when time-averaged constraints are used during the molecular dynamics calculations instead of the conventional restraints (Jrms approximately 0.6 Hz). MD-tar simulations also improve the NMR R factors. This improvement is more evident in the DNA than in the RNA strand, where no indication of conformational flexibility had been obtained. Analysis of the MD-tar trajectories confirms that deoxyriboses undergo pucker transitions between the S and N domain, with the major conformer in the S domain. The ribose moieties in the RNA strand, however, remain in the N domain during the entire simulation. Conformations of deoxyriboses in the intermediate domain near O4'-endo are obtained when the average structure is calculated with conventional NMR restraints. Since these conformations cannot account for the experimental J coupling information, and they only appear in a very low population in the MD-tar ensemble, we conclude that intermediate E sugar puckers are artifacts produced by the attempt to fit all the structural constraints simultaneously when in reality more than one conformer is present. Most structural features of the duplex remain the same in the average structure and in the MD-tar ensemble, e.g., the minor groove width, exhibiting an intermediate value compared with those of canonical A- and B-like structures.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed2006

Probing the importance of hydrogen bonds in the active site of the subtilisin nattokinase by site-directed mutagenesis and molecular dynamics simulation.

Hydrogen bonds occurring in the catalytic triad (Asp32, His64 and Ser221) and the oxyanion hole (Asn155) are very important to the catalysis of peptide bond hydrolysis by serine proteases. For the subtilisin NK (nattokinase), a bacterial serine protease, construction and analysis of a three-dimensional structural model suggested that several hydrogen bonds formed by four residues function to stabilize the transition state of the hydrolysis reaction. These four residues are Ser33, Asp60, Ser62 and Thr220. In order to remove the effect of these hydrogen bonds, four mutants (Ser33-->Ala33, Asp60-->Ala60, Ser62-->Ala62, and Thr220-->Ala220) were constructed by site-directed mutagenesis. The results of enzyme kinetics indicated that removal of these hydrogen bonds increases the free-energy of the transition state (DeltaDeltaG(T)). We concluded that these hydrogen bonds are more important for catalysis than for binding the substrate, because removal of these bonds mainly affects the kcat but not the K(m) values. A substrate, SUB1 (succinyl-Ala-Ala-Pro-Phe-p-nitroanilide), was used during enzyme kinetics experiments. In the present study we have also shown the results of FEP (free-energy perturbation) calculations with regard to the binding and catalysis reactions for these mutant subtilisins. The calculated difference in FEP also suggested that these four residues are more important for catalysis than binding of the substrate, and the simulated values compared well with the experimental values from enzyme kinetics. The results of MD (molecular dynamics) simulations further demonstrated that removal of these hydrogen bonds partially releases Asp32, His64 and Asn155 so that the stability of the transition state decreases. Another substrate, SUB2 (H-D-Val-Leu-Lys-p-nitroanilide), was used for FEP calculations and MD simulations.

Bacillus subtilis↗
PubMed2006

On the application of accelerated molecular dynamics to liquid water simulations.

Our group recently proposed a robust bias potential function that can be used in an efficient all-atom accelerated molecular dynamics (MD) approach to simulate the transition of high energy barriers without any advance knowledge of the potential-energy landscape. The main idea is to modify the potential-energy surface by adding a bias, or boost, potential in regions close to the local minima, such that all transitions rates are increased. By applying the accelerated MD simulation method to liquid water, we observed that this new simulation technique accelerates the molecular motion without losing its microscopic structure and equilibrium properties. Our results showed that the application of a small boost energy on the potential-energy surface significantly reduces the statistical inefficiency of the simulation while keeping all the other calculated properties unchanged. On the other hand, although aggressive acceleration of the dynamics simulation increases the self-diffusion coefficient of water molecules greatly and dramatically reduces the correlation time of the simulation, configurations representative of the true structure of liquid water are poorly sampled. Our results also showed the strength and robustness of this simulation technique, which confirm this approach as a very useful and promising tool to extend the time scale of the all-atom simulations of biological system with explicit solvent models. However, we should keep in mind that there is a compromise between the strength of the boost applied in the simulation and the reproduction of the ensemble average properties.

Algorithms↗
PubMed2004

Beta-hairpin folding mechanism of a nine-residue peptide revealed from molecular dynamics simulations in explicit water.

The beta-hairpin fold mechanism of a nine-residue peptide, which is modified from the beta-hairpin of alpha-amylase inhibitor tendamistat (residues 15-23), is studied through direct folding simulations in explicit water at native folding conditions. Three 300-nanosecond self-guided molecular dynamics (SGMD) simulations have revealed a series of beta-hairpin folding events. During these simulations, the peptide folds repeatedly into a major cluster of beta-hairpin structures, which agree well with nuclear magnetic resonance experimental observations. This major cluster is found to have the minimum conformational free energy among all sampled conformations. This peptide also folds into many other beta-hairpin structures, which represent some local free energy minimum states. In the unfolded state, the N-terminal residues of the peptide, Tyr-1, Gln-2, and Asn-3, have a confined conformational distribution. This confinement makes beta-hairpin the only energetically favored structure to fold. The unfolded state of this peptide is populated with conformations with non-native intrapeptide interactions. This peptide goes through fully hydrated conformations to eliminate non-native interactions before folding into a beta-hairpin. The folding of a beta-hairpin starts with side-chain interactions, which bring two strands together to form interstrand hydrogen bonds. The unfolding of the beta-hairpin is not simply the reverse of the folding process. Comparing unfolding simulations using MD and SGMD methods demonstrate that SGMD simulations can qualitatively reproduce the kinetics of the peptide system.

Amino Acid Sequence↗
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

Spinodal decomposition in thin films: molecular-dynamics simulations of a binary Lennard-Jones fluid mixture.

We use molecular dynamics (MD) to simulate an unstable homogeneous mixture of binary fluids (AB), confined in a slit pore of width D. The pore walls are assumed to be flat and structureless and attract one component of the mixture (A) with the same strength. The pairwise interactions between the particles are modeled by the Lennard-Jones potential, with symmetric parameters that lead to a miscibility gap in the bulk. In the thin-film geometry, an interesting interplay occurs between surface enrichment and phase separation. We study the evolution of a mixture with equal amounts of A and B, which is rendered unstable by a temperature quench. We find that A-rich surface enrichment layers form quickly during the early stages of the evolution, causing a depletion of A in the inner regions of the film. These surface-directed concentration profiles propagate from the walls towards the center of the film, resulting in a transient layered structure. This layered state breaks up into a columnar state, which is characterized by the lateral coarsening of cylindrical domains. The qualitative features of this process resemble results from previous studies of diffusive Ginzburg-Landau-type models [S. K. Das, S. Puri, J. Horbach, and K. Binder, Phys. Rev. E 72, 061603 (2005)], but quantitative aspects differ markedly. The relation to spinodal decomposition in a strictly two-dimensional geometry is also discussed.

Journal Article↗