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At least 469 records · Page 26Linked to original sources
PubMed2003

Molecular dynamics simulations of beta-cyclodextrin in aqueous solution.

Molecular dynamics (MD) simulations of beta-cyclodextrin (beta-CD) have been carried out in aqueous solution at 300 K over a period of about 200 ps using Tripos force field. The atomic trajectories obtained by these simulations have been analysed by means of the occurrence of hydrogen bonds. The MD simulations lead to an association of seven water molecules into the beta-CD cavity which is in a good agreement with X-ray crystallography experiments. This demonstrates that the force field used in the simulations is able to reproduce the experimentally observed hydrophilic-hydrophobic characteristics of beta-CD molecule.

Crystallography, X-Ray↗
PubMed1997

Hydration of an alpha-helical peptide: comparison of theory and molecular dynamics simulation.

We present a statistical mechanical description of biomolecular hydration that accurately describes the hydrophobic and hydrophilic hydration of a model alpha-helical peptide. The local density of water molecules around a biomolecule is obtained by means of a potential-of-mean-force (PMF) expansion in terms of pair- and triplet-correlation functions of bulk water and dilute solutions of nonpolar atoms. The accuracy of the method is verified by comparing PMF results with the local density and site-site correlation functions obtained by molecular dynamics simulations of a model alpha-helix in solution. The PMF approach quantitatively reproduces all features of the peptide hydration determined from the molecular dynamics simulation. Regions of hydrophobic hydration near the C alpha and C beta atoms along the helix are well reproduced. The hydration of exposed polar groups at the N- and C-termini of the helix are also well described by the theory. A detailed comparison of the local hydration by means of site-site radial distribution functions evaluated with the PMF theory shows agreement with the molecular dynamics simulations. The formulation of this theory is general and can be applied to any biomolecular system. The accuracy, speed of computation, and local character of this theory make it especially suitable for studying large biomolecular systems.

Computer Simulation↗
PubMed2004

Thermodynamics and stability of a beta-sheet complex: molecular dynamics simulations on simplified off-lattice protein models.

We have performed discontinuous molecular dynamics simulations of the thermodynamics and stability of a tetrameric beta-sheet complex that contains four identical four-stranded antiparallel beta-sheet peptides. The potential used in the simulation is a hybrid Go-type potential characterized by the bias gap parameter g, an artificial measure of the preference of a model protein for its native state, and the intermolecular contact parameter eta, which measures the ratio of intermolecular to intramolecular native attractions. Despite the simplicity of the model, a complex set of thermodynamic transitions for the beta-sheet complex is revealed that shows there are three distinct oligomer (partially ordered, ordered, and highly ordered beta-sheet complex) states and four noninteracting monomers phases. The thermodynamic properties of the three oligomer states strongly depend on both the size of the intermolecular contact parameter eta and the temperature. The partially ordered beta-sheet complex is made up of four ordered globules and is observed at intermediate to large eta at high temperatures. The ordered beta-sheet complex contains four native beta-sheets and is located at small to intermediate eta at low temperatures in the phase diagram. The highly ordered beta-sheet complex has fully-stiff beta-sheet strands, the same as the global energy minimum structure, and is observed for all eta at low temperatures.

Computer Simulation↗
PubMed2006

Structural characterization of interfacial n-octanol and 3-octanol using molecular dynamic simulations.

Structurally isomeric octanol interfacial systems, water/vapor, 3-octanol/vapor, n-octanol/vapor, 3-octanol/water, and n-octanol/water are investigated at 298 K using molecular dynamics simulation techniques. The present study is intended to investigate strongly associated liquid/liquid interfaces and probe the atomistic structure of these interfaces. The octanol and water molecules were initially placed randomly into a box and were equilibrated using constant pressure techniques to minimize bias within the initial conditions as well as to fully sample the structural conformations of the interface. An interface formed via phase separation during equilibration and resulted in a slab geometry with a molecularly sharp interface. However, some water molecules remained within the octanol phase with a mole fraction of 0.12 after equilibration. The resulting "wet" octanol interfaces were analyzed using density profiles and orientational order parameters. Our results support the hypothesis of an ordered interface only 1 or 2 molecular layers deep before bulk properties are reached for both the 3-octanol and water systems. However, in contrast to most other interfacial systems studied by molecular dynamics simulations, the n-octanol interface extends for several molecular layers. The octanol hydroxyl groups form a hydrogen-bonding network with water which orders the surface molecules toward a preferred direction and produces a hydrophilic/hydrophobic layering. The ordered n-octanol produces an oscillating low-high density of oxygen atoms out of phase with a high-low density of carbon atoms, consistent with an oscillating dielectric. In contrast, the isomeric 3-octanol has only a single carbon-rich layer directly proximal to the interface, which is a result of the different molecular topology. Both 3-octanol and n-octanol roughen the water interface with respect to the water/vapor interface. The "wet" octanol phases, in the octanol/water systems reach bulk properties in a shorter distance than the "dry" octanol/vapor interfaces.

1-Octanol↗
PubMed2004

Assembly and kinetic folding pathways of a tetrameric beta-sheet complex: molecular dynamics simulations on simplified off-lattice protein models.

We have performed discontinuous molecular dynamic simulations of the assembly and folding kinetics of a tetrameric beta-sheet complex that contains four identical four-stranded antiparallel beta-sheet peptides. The potential used in the simulation is a hybrid Go-type potential characterized by the bias gap parameter g, an artificial measure of a model protein's preference for its native state, and the intermolecular contact parameter eta, which measures the ratio of intermolecular to intramolecular native attractions. The formation of the beta-sheet complex and its equilibrium properties strongly depend on the size of the intermolecular contact parameter eta. The ordered beta-sheet complex in the folded state and nonaligned beta-sheets or tangled chains in the misfolded state are distinguished by measuring the squared radius of gyration Rg2 and the fraction of native contacts Q. The folding yield for the folded state is high at intermediate values of eta, but is low at both small and large values of eta. The folded state at small eta is liquid-like, but is solid-like at both intermediate and large eta. The misfolded state at small eta contains nonaligned beta-sheets and tangled chains with poor secondary structure at large eta. Various folding pathways via dimeric and trimeric intermediates are observed, depending on eta. Comparison with experimental results on protein aggregation indicates that intermediate eta values are most appropriate for modeling fibril formation and small eta values are most appropriate for modeling the formation of amorphous aggregates.

Binding Sites↗
PubMed2002

Molecular dynamics simulations of mixed micelles modeling human bile.

Extensive molecular dynamics (MD) simulations of binary systems of phospholipids and bile salts, a model for human bile, have been performed. Recent progress in hardware and software development allows simulation of the spontaneous aggregation of the constituents into small mixed micelles, in agreement with experimental observations. The MD simulations reveal the structure of these micelles at atomic detail. The phospholipids are packed radially with their headgroups at the surface and the hydrophobic tails pointing toward the micellar center. The bile salts act as wedges between the phospholipid headgroups, with their hydrophilic sides exposed to the aqueous environment. The structure of the micelles strongly resembles the previously proposed radial shell model. Simulations including small fractions of cholesterol reveal how cholesterol is solubilized inside these mixed micelles without changing their overall structure.

Bile↗
PubMed2001

Refinement of the NMR structures of alpha-conotoxin MI using molecular dynamics simulation with explicit solvent water and a full molecular force field.

Three NMR structures of alpha-conotoxin MI, a potent antagonist of the nicotinic acetylcholine receptor, have been refined using molecular dynamics (MD) simulation with explicit water. Although the convergence of the NMR structures of alpha-conotoxin MI was not sufficient to provide detailed structural features, the average structures obtained from MD simulations converged to one conformation, providing structural characteristics. The resulting structure was also found to be consistent with the results of amide proton-exchange experiments. These results demonstrate that MD simulation with explicit solvent water is very useful in refining NMR structures.

Conotoxins↗
PubMed1999

Molecular dynamics simulations of human prion protein: importance of correct treatment of electrostatic interactions.

Molecular dynamics simulations have been used to investigate the dynamical and structural behavior of a homology model of human prion protein HuPrP(90-230) generated from the NMR structure of the Syrian hamster prion protein ShPrP(90-231) and of ShPrP(<90-231) itself. These PrPs have a large number of charged residues on the protein surface. At the simulation pH 7, HuPrP(90-230) has a net charge of -1 eu from 15 positively and 14 negatively charged residues. Simulations for both PrPs, using the AMBER94 force field in a periodic box model with explicit water molecules, showed high sensitivity to the correct treatment of the electrostatic interactions. Highly unstable behavior of the structured region of the PrPs (127-230) was found using the truncation method, and stable trajectories could be achieved only by including all the long-range electrostatic interactions using the particle mesh Ewald (PME) method. The instability using the truncation method could not be reduced by adding sodium and chloride ions nor by replacing some of the sodium ions with calcium ions. The PME simulations showed, in accordance with NMR experiments with ShPrP and mouse PrP, a flexibly disordered N-terminal part, PrP(90-126), and a structured C-terminal part, PrP(127-230), which includes three alpha-helices and a short antiparallel beta-strand. The simulations showed some tendency for the highly conserved hydrophobic segment PrP(112-131) to adopt an alpha-helical conformation and for helix C to split at residues 212-213, a known disease-associated mutation site (Q212P). Three highly occupied salt bridges could be identified (E146/D144<-->R208, R164<-->D178, and R156<-->E196) which appear to be important for the stability of PrP by linking the stable main structured core (helices B and C) with the more flexible structured part (helix A and strands A and B). Two of these salt bridges involve disease-associated mutations (R208H and D178N). Decreased PrP stability shown by protein unfolding experiments on mutants of these residues and guanidinium chloride or temperature-induced unfolding studies indicating reduced stability at low pH are consistent with stabilization by salt bridges. The fact that electrostatic interactions, in general, and salt bridges, in particular, appear to play an important role in PrP stability has implications for PrP structure and stability at different pHs it may encounter physiologically during normal or abnormal recycling from the pH neutral membrane surface into endosomes or lysomes (acidic pHs) or in NMR experiments (5.2 for ShPrP and 4.5 for mouse PrP).

Amino Acid Sequence↗
PubMed2004

Structure and axis curvature in two dA6 x dT6 DNA oligonucleotides: comparison of molecular dynamics simulations with results from crystallography and NMR spectroscopy.

Molecular dynamics (MD) simulations have been performed on the A6 containing DNA dodecamers d(GGCAAAAAACGG) solved by NMR and d(CGCAAAAAAGCG) solved by crystallography. The experimental structures differ in the direction of axis bending and in other small but important aspects relevant to the DNA curvature problem. Five nanosecond MD simulations of each sequence have been performed, beginning with both the NMR and crystal forms as well as canonical B-form DNA. The results show that all simulations converge to a common form in close proximity to the observed NMR structure, indicating that the structure obtained in the crystal is likely a strained form due to packing effects. A-tracts in the MD model are essentially straight. The origin of axis curvature is found at pyrimidine-purine steps in the flanking sequences.

Adenine↗
PubMed1994

Molecular dynamics simulations of oligonucleotides in solution: visualization of intrinsic curvature.

We have undertaken molecular dynamics simulations on the d(CGCAAAAAAGCG).d(CGCTTTTTTGCG) dodecamer in solution. In this study, we focus on aspects of conformation and dynamics, including the possibility of cross-strand hydrogen bonds. We compare our results with those from crystallography as well as infrared, Raman and NMR spectroscopy and cyclization kinetics. Our method of analysis allows us to visualise the curvature of the helix as a function of time during the simulation. We find that the major distortions of the helix axis path occur at the junctions between the (essentially straight) A-tract and the CG- and GC-tracts, although at one junction this is due to hyperflexibility (i.e., regions of high flexibility with no preferred direction of curvature), while at the other junction a static curvature is found (i.e., a preferred, sustained direction of curvature).

Base Sequence↗
PubMed2004

Molecular dynamics simulations of structural changes during procaspase 3 activation.

Molecular dynamics (MD) simulations of the structural rearrangements on the pathway leading to procaspase 3 activation are presented. A retrostructural approach is used to build procaspase 3 from mature caspase 3. The peptide bond that is cleaved during enzyme maturation is gradually reformed during the MD simulation and the most relevant structural changes that occur as a consequence are analyzed. The main structural features that characterize this procaspase 3 model are compared with the available X-ray structure of procaspase 7 as the only zymogen structure that has been crystallised so far. The MD simulations indicate that in the free caspase 3, the flexible selectivity loop is already preorganized to accomodate the substrate. Such a preorganization is not present in either monomeric caspase 3 or in the procaspase 3 dimer, indicating that the structure of the selectivity loop is highly sensitive to perturbations.

Caspase 3↗
PubMed1991

Mass-weighted molecular dynamics simulation and conformational analysis of polypeptide.

Atomic motions in protein molecules have been studied by molecular dynamics (MD) simulations; dynamics simulation methods have also been employed in conformational studies of polypeptide molecules. It was found that when atomic masses are weighted, the molecular dynamics method can significantly increase the sampling of dihedral conformation space in such studies, compared to a conventional MD simulation of the same total simulation time length. Herein the theoretical study of molecular conformation sampling by the molecular dynamics-based simulation method in which atomic masses are weighted is reported in detail; moreover, a numerical scheme for analyzing the extensive conformational sampling in the simulation of a tetrapeptide amide molecule is presented. From numerical analyses of the mass-weighted molecular dynamics trajectories of backbone dihedral angles, low-resolution structures covering the entire backbone dihedral conformation space of the molecule were determined, and the distribution of rotationally stable conformations in this space were analyzed quantitatively. The theoretical analyses based on the computer simulation and numerical analytical methods suggest that distinctive regimes in the conformational space of the peptide molecule can be identified.

Amino Acid Sequence↗
PubMed1991

Mass-weighted molecular dynamics simulation of cyclic polypeptides.

A modified molecular dynamics (MD) method in which atomic masses are weighted was developed previously for studying the conformational flexibility of neuroregulating tetrapeptide Phe-Met-Arg-Phe-amide (FMRF-amide). The method has now been applied to longer and constrained molecules, namely a disulfide-linked cyclic hexapeptide, c[CYFQNC], and its linear and "pseudo-cyclic" analogues. The sampling of dehedral conformational space of teh linear hexapeptide in mass-weighted MD simulations was found to be improved significantly over conventional MD simulations, as in the case of the shorter FMRF-amide molecule studied previously. In the cyclic hexapeptide, the internal constraint of the molecule due to the intramolecular disulfide bond (hence the absence of free terminals in the molecule) does not adversely affect the significant improvement of conformational sampling in mass-weighted MD simulations over normal MD simulations. The pseudo-cyclic polypeptide is identical to the linear CYFQNC molecule in amino acid sequence (i.e., side chains of the cysteine residues are reduced), but the positions of its two terminal heavy atoms were held fixed in space such that the molecule has a nearly cyclic conformation. For this molecule, the mass-weighted MD simulation generated a wide range of polypeptide backbone conformations covering the internal dihedral degrees of freedom; moreover, the physical space of the pseudo-cyclic structure was also sampled in a complete revolution of the entire molecular fragment about the two fixed termini during the simulation. These characteristics suggest that mass-weighted MD can also be an extremely useful method for conformational analyses of constrained molecules and, in particular, for modeling loops on protein surfaces.

Amino Acid Sequence↗
PubMed2005

Large scale molecular dynamics simulation of native and mutant dihydropteroate synthase-sulphanilamide complexes suggests the molecular basis for dihydropteroate synthase drug resistance.

Antibiotic resistance is hampering the efficacy of drugs in the treatment of several pathological infections. Dihydropteroate synthase (DHPS) has been targeted by sulphonamide inhibitors for the past 60 years and has developed different amino acid mutations to survive sulpha drug action. We couple homology modelling techniques and massively parallel molecular dynamics simulations to study both the drug-bound and apo forms of native and mutant DHPS. Simulations of the complex between sulphanilamide and Streptomyces pneumoniae, DHPS shows how sulphanilamide is able to position itself close to 6-hydroxymethyl-7, 8-dihydropteridine-phosphate in a suitable position for the enzymatic transformation whereas in the mutant complex the sulpha drug is expelled from the catalytic site. Our simulations, therefore, provide insight into the molecular basis for drug resistance with S. pneumoniae DHPS.

Anti-Bacterial Agents↗
PubMed1994

Structure and dynamics of the active site gorge of acetylcholinesterase: synergistic use of molecular dynamics simulation and X-ray crystallography.

The active site of acetylcholinesterase (AChE) from Torpedo californica is located 20 A from the enzyme surface at the bottom of a narrow gorge. To understand the role of this gorge in the function of AChE, we have studied simulations of its molecular dynamics. When simulations were conducted with pure water filling the gorge, residues in the vicinity of the active site deviated quickly and markedly from the crystal structure. Further study of the original crystallographic data suggests that a bis-quaternary decamethonium (DECA) ion, acquired during enzyme purification, residues in the gorge. There is additional electron density within the gorge that may represent small bound cations. When DECA and 2 cations are placed within the gorge, the simulation and the crystal structure are dramatically reconciled. The small cations, more so than DECA, appear to stabilize part of the gorge wall through electrostatic interactions. This part of the gorge wall is relatively thin and may regulate substrate, product, and water movement through the active site.

Acetylcholinesterase↗
PubMed2001

Validation of protein-unfolding transition states identified in molecular dynamics simulations.

Experimental and simulation studies can complement each other nicely in the area of protein folding. Experiment reports on the average properties of a large ensemble (approx. 10(17)-10(19) molecules), typically over time. Molecular dynamics simulations, on the other hand, provide detailed information for a single molecule, a component of the ensemble. By combining these approaches we can obtain not only a more complete picture of folding, but we can also take advantage of the strengths of different methods. For example, experiment cannot provide molecular structures. Molecular dynamics simulations can provide such information, but the simulations are meaningless without a linked experiment. Thus, the interrelated nature of simulation in assessing experimental assumptions and in providing structures to augment energetic descriptions, and experiment in judging whether the simulations are reasonable, provides more confidence in the resulting information about folding. This combination yields tested and testable molecular models of states that evade characterization by conventional methods. Therefore, we have explored the combined use of these methods to map folding/unfolding pathways at atomic resolution, in collaboration with Alan Fersht. Here we focus on chymotrypsin inhibitor 2, a small single-domain, two-state folding protein.

In Vitro Techniques↗
PubMed2005

Stochastic boundary molecular dynamics simulation of L-ribose in the active site of Actinoplanes missouriensis xylose isomerase and its Val135Asn mutant with improved reaction rate.

We used molecular dynamics simulations to study how a non-natural substrate, L-ribose, interacts with the active site of Actinoplanes missouriensis xylose isomerase. The simulations showed that L-ribose does not stay liganded in the active site in the same way as D-xylose, in which the oxygens O2 and O4 are liganded to the metal M1. The oxygen O4 of L-ribose moved away from the metal M1 to an upside down position. Furthermore, the distances of the carbons C1 and C2 of L-ribose to the catalytic metal M2 were higher than in the case of D-xylose. These findings explain the extremely low reaction rate of xylose isomerase with L-ribose. The mutation V135N close to the C5-OH of the substrate increased the reaction efficiency 2- to 4-fold with L-ribose. V135N did not affect the reaction with D-xylose and L-arabinose, whereas the reaction with D-glucose was impaired, probably due to a hydrogen bond between Asn-135 and the substrate. When L-ribose was the substrate, Asn-135 formed a hydrogen bond to Glu-181. As a consequence, O4 of L-ribose stayed liganded to the metal M1 in the V135N mutant in molecular dynamics simulations. This explains the decreased K(m) of the V135N mutant with L-ribose.

Aldose-Ketose Isomerases↗
PubMed1997

Threonine6-bradykinin: molecular dynamics simulations in a biphasic membrane mimetic.

The natural peptide [Thr6]-bradykinin, Arg1-Pro2-Pro3-Gly4-Phe5-Thr6-Pro7-Phe8-Arg9, has been conformationally examined by molecular dynamics simulations using a two-phase box consisting of H2O and CCl4 to mimic the micellar environment utilized in the 1H-NMR studies. The different conformations generated from distance geometry calculations were refined with extensive molecular dynamics simulations. The resulting conformations provide additional structural insight into the differing biological activities of native bradykinin and [Thr6]-bradykinin, produced by the one conservative substitution Thr6 for Ser6. In addition, the simulations give some indication of the interaction of the peptide with the biphasic, hydrophilic/hydrophobic environment of the micelle. Such information is vital given the accumulating data indicating that the peptide first interacts with the membrane before the membrane-bound receptor. The structures of membrane-bound [Thr6]-bradykinin developed here provide experimental support for the interaction of residues 7 and 8 with the core of the membrane-bound receptor and the N-terminus and C-terminal arginine interacting with the extracellular portion of the receptor.

Bradykinin↗