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PubMed2023

A new horizon in the phosphorylated sites of AGA: the structural impact of C163S mutation in aspartylglucosaminuria through molecular dynamics simulation.

Aspartylglucosaminuria (AGU) is a lysosomal storage disorder caused by insufficient aspartylglucosaminidase (AGA) activity leading to chronic neurodegeneration. We utilized the PhosphoSitePlus tool to identify the AGA protein's phosphorylation sites. The phosphorylation was induced on the specific residue of the three-dimensional AGA protein, and the structural changes upon phosphorylation were studied via molecular dynamics simulation. Furthermore, the structural behaviour of C163S mutation and C163S mutation with adjacent phosphorylation was investigated. We have examined the structural impact of phosphorylated forms and C163S mutation in AGA. Molecular dynamics simulations (200 ns) exposed patterns of deviation, fluctuation, and change in compactness of Y178 phosphorylated AGA protein (Y178-p), T215 phosphorylated AGA protein (T215-p), T324 phosphorylated AGA protein (T324-p), C163S mutant AGA protein (C163S), and C163S mutation with Y178 phosphorylated AGA protein (C163S-Y178-p). Y178-p, T215-p, and C163S mutation demonstrated an increase in intramolecular hydrogen bonds, leading to greater compactness of the AGA forms. Principle component analysis (PCA) and Gibbs free energy of the phosphorylated/C163S mutation structures exhibit transition in motion/orientation than Wild type (WT). T215-p may be more dominant among these than the other studied phosphorylated forms. It might contribute to hydrolyzing L-asparagine functioning as an asparaginase, thereby regulating neurotransmitter activity. This study revealed structural insights into the phosphorylation of Y178, T215, and T324 in AGA protein. Additionally, it exposed the structural changes of the C163S mutation and C163S-Y178-p of AGA protein. This research will shed light on a better understanding of AGA's phosphorylated mechanism.Communicated by Ramaswamy H. Sarma.

Molecular Dynamics Simulation↗
PubMed2005

Molecular dynamics simulation of a perylene-derivative Langmuir film.

We performed a series of molecular dynamics simulations of an N,N'-di-n-butyl-3,4:9,10-perylene tetracarboxydiimide (BuPTCD) Langmuir film. The film was studied at three surface areas (0.38, 0.40, and 0.45 nm2 molecule(-1)) using model systems consisting of one BuPTCD monolayer on each side of a 6.0-nm-thick water slab. On the basis of geometrical reasoning and surface pressure results, it was found that perylene molecules seem to be oriented mainly head-on toward the water surface. On the other hand, the average orientation of the perylene tetracarboxidiimide moiety during simulations indicated that molecular alignment is not simple, changing from tilted face-on to tilted head-on during compression. The change in orientation of BuPTCD molecules was accompanied by the thickening of the film as the area decreased. Films also became more orderly at small surface areas, mostly at the rigid perylene core. BuPTCD molecules are not evenly hydrated, with very few solvent molecules hydrating the hydrophobic tails, whereas a considerable number of water molecules were hydrogen bonded to diimide oxygen atoms. Besides, the residence times of water molecules around perylene atomic sites increased from the terminal methyl groups to the diimide oxygen atoms. Finally, the electric potential profile across the monolayer was found to depend on the area occupied by each molecule, indicating that properties of the films may vary considerably with the area occupied by each molecule. Altogether, the molecular description arising from our computer simulations suggests which structural patterns may be found in these films depending on the surface density of perylene molecules.

Journal Article↗
PubMed2003

Molecular dynamics simulations of end-to-end contact formation in hydrocarbon chains in water and aqueous urea solution.

We probe the urea-denaturation mechanism using molecular dynamics simulations of an elementary "folding" event, namely, the formation of end-to-end contact in the linear hydrocarbon chain (HC) CH(3)(CH(2))(18)CH(3). Electrostatic effects are examined using a model HC in which one end of the chain is positively charged (+0.2e) and the other contains a negative charge (-0.2e). For these systems multiple transitions between "folded" (conformations in which the chain ends are in contact) and "unfolded" (end-to-end contact is broken) can be observed during 4 ns molecular dynamics simulations. In water and 6 M aqueous urea solution HC and the charged HC fluctuate between collapsed globular conformations and a set of expanded structures. The collapsed conformation adopted by the HC in water is slightly destablized in 6 M urea. In contrast, the end-to-end contact is disrupted in the charged HC only in aqueous urea solution. Despite the presence of a large hydrophobic patch, on length scales on the order of approximately 8-10 A "denaturation" (transition to the expanded unfolded state) occurs by a direct interaction of urea with charges on the chain ends. The contiguous patch of hydrophobic moieties leads to "mild dewetting", which becomes more pronounced in the charged HC in 6 M aqueous urea solution. Our simulations establish that the urea denaturation mechanism is most likely electrostatic in origin.

Computer Simulation↗
PubMed2001

Dynamics-function correlation in Cu, Zn superoxide dismutase: a spectroscopic and molecular dynamics simulation study.

A single mutation (Val29-->Gly) at the subunit interface of a Cu, Zn superoxide dismutase dimer leads to a twofold increase in the second order catalytic rate, when compared to the native enzyme, without causing any modification of the structure or the electric field distribution. To check the role of dynamic processes in this catalytic enhancement, the flexibility of the dimeric protein at the subunit interface region has been probed by the phosphorescence and fluorescence properties of the unique tryptophan residue. Multiple spectroscopic data indicate that Trp83 experiences a very similar, and relatively hydrophobic, environment in both wild-type and mutant protein, whereas its mobility is distinctly more restrained in the latter. Molecular dynamics simulation confirms this result, and provides, at the molecular level, details of the dynamic change felt by tryptophan. Moreover, the simulation shows that the loops surrounding the active site are more flexible in the mutant than in the native enzyme, making the copper more accessible to the incoming substrate, and being thus responsible for the catalytic rate enhancement. Evidence for increased, dynamic copper accessibility also comes from faster copper removal in the mutant by a metal chelator. These results indicate that differences in dynamic, rather than structural, features of the two enzymes are responsible for the observed functional change.

Amino Acid Sequence↗
PubMed2001

Force-field parametrization and molecular dynamics simulations of p-menthan-3,9-diols: a family of amphiphilic compounds derived from terpenoids.

A set of amphiphilic p-menthan-3,9-diols have been investigated by molecular dynamics simulations. These are four stereoisomers than can be specifically obtained from two terpenoids widely used in biorganic chemistry. For this purpose, the p-menthan-3,9-diols have been explicitly parametrized using both semiempirical and ab initio quantum mechanical calculations. The reliability of these parameters has been validated by predicting different molecular and thermodynamic properties. Molecular dynamics simulations in aqueous solution have been performed with the new parameters. The results provide useful insights about the conformational properties of this family of compounds and the formation of intra- and intermolecular hydrogen bonds.

Drug Design↗
PubMed2000

Nonequilibrium molecular dynamics simulations of transport and separation of gas mixtures in nanoporous materials

The nonequilibrium molecular dynamics simulations of transport and separation of a binary gas mixture through a porous membrane with interconnected pores of distributed sizes are reported. The membrane is modeled by a three-dimensional disordered molecular network of interconnected pores consisting of tens of thousands of atoms, based on a Voronoi tessellation of space. Results are presented for transport and adsorption of the gases, including the existence of an optimal pore structure for maximum separation of the gases.

Journal Article↗
PubMed1999

Vibrational population relaxation of carbon monoxide in the heme pocket of photolyzed carbonmonoxy myoglobin: comparison of time-resolved mid-IR absorbance experiments and molecular dynamics simulations.

The vibrational energy relaxation of carbon monoxide in the heme pocket of sperm whale myoglobin was studied by using molecular dynamics simulation and normal mode analysis methods. Molecular dynamics trajectories of solvated myoglobin were run at 300 K for both the delta- and epsilon-tautomers of the distal His-64. Vibrational population relaxation times of 335 +/- 115 ps for the delta-tautomer and 640 +/- 185 ps for the epsilon-tautomer were estimated by using the Landau-Teller model. Normal mode analysis was used to identify those protein residues that act as the primary "doorway" modes in the vibrational relaxation of the oscillator. Although the CO relaxation rates in both the epsilon- and delta-tautomers are similar in magnitude, the simulations predict that the vibrational relaxation of the CO is faster in the delta-tautomer with the distal His playing an important role in the energy relaxation mechanism. Time-resolved mid-IR absorbance measurements were performed on photolyzed carbonmonoxy hemoglobin (Hb(13)CO). From these measurements, a T(1) time of 600 +/- 150 ps was determined. The simulation and experimental estimates are compared and discussed.

Carbon Monoxide↗
PubMed2001

Molecular dynamics simulations of urea and thermal-induced denaturation of S-peptide analogue.

Molecular dynamics simulations of the S-peptide analogue AETAAAKFLREHMDS in water at 278 and 358 K, and in 8 M urea at 278 K were performed. The results show agreement with experiments. The helix is stable at low temperature (278 K), while at 358 K, unfolding is observed. The effects of urea on protein stability have been studied. The data support a model in which urea denatures proteins by: (1) diminishing the hydrophobic effect by displacing water molecules from the solvent shell around nonpolar groups; and (2) binding directly to amide units (NH and CO groups) via hydrogen bonds. The results of cluster analysis and essential dynamics analysis suggest that the mechanism of urea and thermal-induced denaturation may not be the same.

Amino Acid Sequence↗
PubMed2004

The folding pathway of ubiquitin from all-atom molecular dynamics simulations.

The folding (unfolding) pathway of ubiquitin is probed using all-atom molecular dynamics simulations. We dissect the folding pathway using two techniques: first, we probe the folding pathway of ubiquitin by calculating the evolution of structural properties over time and second, we identify the rate determining transition state for folding. The structural properties that we look at are hydrophobic solvent accessible surface area (SASA) and Calpha-root-mean-square deviation (rmsd). These properties on their own tell us relatively little about the folding pathway of ubiquitin; however, when plotted against each other, they become powerful tools for dissecting ubiquitin's folding mechanism. Plots of Calpha-rmsd against SASA serve as a phase space trajectories for the folding of ubiquitin. In this study, these plots show that ubiquitin folds to the native state via the population of an intermediate state. This is shown by an initial hydrophobic collapse phase followed by a second phase of secondary structure arrangement. Analysis of the structure of the intermediate state shows that it is a collapsed species with very little secondary structure. In reconciling these observations with recent experimental data, the transition that we observe in our simulations from the unfolded state (U) to the intermediate state (I) most likely occurs in the dead-time of the stopped flow instrument. The folding pathway of ubiquitin is probed further by identification of the rate-determining transition state for folding. The method used for this is essential dynamics, which utilizes a principal component analysis (PCA) on the atomic fluctuations throughout the simulation. The five transition state structures identified in silico are in good agreement with the experimentally determined transition state. The calculation of phi-values from the structures generated in the simulations is also carried out and it shows a good correlation with the experimentally measured values. An initial analysis of the denatured state shows that it is compact with fluctuating regions of nonnative secondary structure. It is found that the compactness in the denatured state is due to the burial of some hydrophobic residues. We conclude by looking at a correlation between folding kinetics and residual structure in the denatured state. A hierarchical folding mechanism is then proposed for ubiquitin.

Computer Simulation↗
PubMed1997

Molecular dynamics simulations of the unfolding of barnase in water and 8 M aqueous urea.

Molecular dynamics simulations of barnase have been conducted both in water and in 8 M urea solution for 500 ps at 25 degrees C and for 2000 ps at 85 degrees C. The final structure of the aqueous simulation at room temperature matches closely the structure obtained by NMR and the experimentally observed protections from isotopic exchange. The comparison of the structures generated by the aqueous simulation at 85 degrees C reveals a trajectory composed of groups of geometrically related structures separated by narrow regions of rapid change in structure. The first of these regions displays changes in backbone rmsd to the crystal structure and solvent-accessible area suggestive of a transition state, while the properties observed during the final 300 ps of the simulation are consistent with a stable intermediate. These assignments were confirmed by calculation of the "progress along the reaction coordinate" phi-values using an empirical equation based on a linear response method. The pathway of unfolding defined in this fashion agrees well with the experimental results of site-directed mutagenesis in terms of secondary structure content of the transition state and the intermediate and reproduces the relative stability of the different elements of secondary structure. The results of the simulations in urea suggest a mechanism at the molecular level for its well-known enhancement of the denaturation of proteins. The analysis of radial distribution functions shows that the first solvation shell of the protein is enriched in urea relative to the bulk solvent. The displacement of water molecules allows greater exposure of hydrophobic side chains, as witnessed particularly in the analysis of solvent-accessible surface areas at the higher temperature. Almost all urea molecules in the first shell form at least one hydrogen bond with the protein. They provide a more favorable environment for accommodation of the remaining water molecules, and they facilitate the separation of secondary structure elements by acting as a bridge between groups previously forming intraprotein hydrogen bonds.

Bacterial Proteins↗
PubMed2004

Discrete molecular dynamics simulations of peptide aggregation.

We study the aggregation of peptides using the discrete molecular dynamics simulations. Specifically, at temperatures above the alpha-helix melting temperature of a single peptide, the model peptides aggregate into a multilayer parallel beta-sheet structure. This structure has an interstrand distance of 4.8 A and an intersheet distance of 10 A, which agree with experimental observations. Our model explains these results as follows: hydrogen-bond interactions give rise to the interstrand spacing in beta sheets, while Gō interactions between side chains make beta strands parallel to each other and allow beta sheets to pack into layers. An important feature of our results is that the aggregates contain free edges, which may allow for further aggregation of model peptides to form elongated fibrils.

Amyloid beta-Peptides↗
PubMed2002

Molecular dynamics simulation of the SH3 domain aggregation suggests a generic amyloidogenesis mechanism.

We use molecular dynamics simulation to study the aggregation of Src SH3 domain proteins. For the case of two proteins, we observe two possible aggregation conformations: the closed form dimer and the open aggregation state. The closed dimer is formed by "domain swapping"-the two proteins exchange their RT-loops. All the hydrophobic residues are buried inside the dimer so proteins cannot further aggregate into elongated amyloid fibrils. We find that the open structure-stabilized by backbone hydrogen bond interactions-packs the RT-loops together by swapping the two strands of the RT-loop. The packed RT-loops form a beta-sheet structure and expose the backbone to promote further aggregation. We also simulate more than two proteins, and find that the aggregate adopts a fibrillar double beta-sheet structure, which is formed by packing the RT-loops from different proteins. Our simulations are consistent with a possible generic amyloidogenesis scenario.

Amino Acid Sequence↗
PubMed1997

Molecular dynamics simulations of the N-linked oligosaccharide of the lectin from Erythrina corallodendron.

Molecular dynamics simulations have been used to model the flexibility of the seven-sugar oligosaccharide of the lectin from Erythrina corallodendron in three separate simulations: one of the isolated oligosaccharide in vacuo, one of the oligosaccharide in solution and one of the oligosaccharide linked to the protein in solution. Adiabatic conformational energy maps were prepared for each of the disaccharide linkages as a means of interpreting the observed dynamics and conformational averages in terms of intramolecular energy. The inclusion of aqueous solvent molecules appears to be necessary to reproduce the experimental conformational behavior, which also cannot be predicted well from conformational energy maps for the disaccharide linkages alone. The crystallographically determined conformation does not appear to be induced by the crystal dimerization, but is rather stable in solution. The build-up of fluctuations along the successive linkages of the oligosaccharide is significant and would be sufficient to prevent branch residues from being located in most crystal structure determinations. Good general agreement between the calculated solution structure and the average structure determined by NMR was found for most of the oligosaccharide linkages.

Carbohydrate Conformation↗
PubMed1992

FOCUS: a program for analyzing molecular dynamics simulations, featuring digital signal-processing techniques.

FOCUS is a program for analyzing molecular dynamics simulations. It enables the researcher to monitor structural and energetic properties during the trajectory, and to calculate the corresponding statistical averages, correlation functions and Fourier transforms. In addition to these conventional methods, the program also utilizes novel methods based on digital signal-processing techniques to characterize the various motions. The characteristic frequencies in the system are revealed by the frequency distribution function g(v), which is calculated from the Fourier transform of the atomic coordinates. A filtering technique is employed to remove uninteresting motion (e.g., high-frequency bond stretching) while retaining and focusing on important motion (e.g., low-frequency conformational motion). The filtering technique enables fast display of slow events without getting a blurry or jittery picture due to the high-frequency motions. Another new way for analyzing the motion is by extracting "characteristic modes" and associated frequencies. This yields a pictorial description of the oscillatory motions in a manner analogous to normal mode analysis.

Acetamides↗
PubMed2006

Catalyzed decomposition of urea. Molecular dynamics simulations of the binding of urea to urease.

We present the results of molecular dynamics simulations on the urea/urease system. The starting structure was prepared from the 2.0 A crystal structure of Benini et al. [(1999) Struct. Folding Des. 7, 205-216] of DAP-inhibited urease (PDB code ), and the trimeric structure (2479 residues) resulted in 180K atoms after solvation by water. The force field parameters were derived using the bonded model approach described by Hoops et al. [(1991) J. Am. Chem. Soc. 113, 8262-8270]. Three different systems were analyzed, each one modeling a different protonation pattern for the His320 and His219 residues. In each case, the three monomers of urease have been analyzed separately. The time-averaged structures observed in the three monomers suggest that urease could follow two different competitive mechanisms. A "protein-assisted proton transfer" mechanism points to Asp221 as crucial for catalysis. An "Asp-mediated proton transfer" involves the transfer of a proton from the bridging OH to an NH2 moiety of urea, assisted by Asp360 in the active site. The impact of the simulation results on our understanding of urease catalysis is discussed in detail.

Bacillus↗
PubMed1994

Molecular dynamics simulations of trp apo- and holorepressors: domain structure and ligand-protein interaction.

Molecular dynamics simulations of the apo- and holo-forms of the trp-repressor protein were performed under extensively solvated conditions in order to elucidate their dynamic structures and ligand-protein interactions. The root mean square fluctuations calculated from the trajectories agreed with those calculated from X-ray temperature factors. Distance, distance fluctuation, and dynamic cross-correlation maps were drawn to provide information on the dynamic structures and communications among the domains. A three-domain format has been proposed for the crystal structure (Zhang et al., Nature 327:591-597, 1987); namely, helices A-C and F of both subunits make up a central core, and D and E of each subunit forms a DNA binding head. The results of the simulations were mostly consistent with the three-domain format. However, helix F was more flexible and freer than other parts of the central core. The turn DE, the helix-turn-helix DNA binding motif, was free from interactions and correlations with other domains in both forms of the repressor. A comparison of the simulations of the aporepressor and holorepressor showed that tryptophan binding made the DNA-binding helix D more flexible but helix F less flexible. Several amino acid residues in contact with the bound tryptophan were identified as making concerted motions with it. Interaction energies between the corepressor and the amino acid residues of the protein were analyzed; the results were mostly consistent with the mutational experiments.

Amino Acid Sequence↗
PubMed2005

Molecular dynamics simulation of paracetamol molecules ordering around glycogen.

By the use of classical atomistic molecular dynamics simulations, we demonstrate that paracetamol molecules exist in a highly ordered phase in the presence of a glycogen substrate at 317 K whereas the paracetamol fluid exists in an isotropic phase in the absence of the glycogen substrate at the same temperature. This result further validates the studies made on polysaccharide regarding its abilities to promote nucleation of paracetamol via liquid preordering. As little is known regarding liquid ordering induced by a polymeric substrate, we seek to explore the ordering mechanism from an energy perspective. This is accomplished using conformation mappings. Our analysis shows that the conformation space accessible to the paracetamol molecule at 317 K in the vicinity of glycogen is smaller than the one in the absence of glycogen. An investigation on the orientation of the dipole moments of the glycogen monomers and paracetamol molecules were carried out as well. From the investigations, we show that dipolar interactions play an important role in the ordering process. These studies bear significance to the understanding of the ordering process as well as the promotion and effective control of the nucleation rate.

Acetaminophen↗
PubMed1997

Molecular dynamics simulation study of DNA dodecamer d(CGCGAATTCGCG) in solution: conformation and hydration.

A molecular dynamics simulation of the dodecamer duplex d(CGCGAATTCGCG) using the particle mesh Ewald sum assumed a B-conformation remarkably close to the observed X-ray structure. The Ewald summation method effectively eliminates the usual "cut-off" of long-range interactions and allowed us to evaluate the full effect of the electrostatic forces. This simulation showed remarkable agreement with the Dickerson X-ray structure in both average structure and B-factors; within the EcoRI site itself, the rms deviation between the average theoretical and observed structures was 1.1 A. The width of the minor groove fluctuated between a wide and narrow configuration with the latter corresponding closely to the X-ray structure. The simulation also suggested a strong sequence-dependent signature on the minor groove width in both wide and narrow conformers. Hydration shells in both the major and minor grooves were observed. The "spine of hydration" in the minor groove was clear. In the major groove the first hydration shell appears to be a ribbon-like structure that reproduces the principal features of observed X-ray structures; subtle variations of this hydration pattern suggest sequence dependencies. Sequence-dependent features were also examined for helical and other geometric parameters. The successful reproduction of many experimentally observed fine structural features shows that the Ewald summation significantly improves the fidelity of the calculations.

Crystallography, X-Ray↗