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At least 1,243 records · Page 69Linked to original sources
PubMed1996

Compared structures of the free nicotinic acetylcholine receptor main immunogenic region (MIR) decapeptide and the antibody-bound [A76]MIR analogue: a molecular dynamics simulation from two-dimensional NMR data.

Monoclonal antibodies against the main immunogenic region (MIR) of the muscle acetylcholine receptor (AChR) are capable of inducing experimental myasthenia gravis (MG) in animals. The epitope of these antibodies has been localized between residues 67 and 76 of the AChR alpha-subunit. The conformation in solution of the Torpedo californica MIR peptide and of its [A76] MIR analogue have been analyzed using molecular modeling based on nmr interproton distances and J-derived phi dihedral angles. Molecular dynamics simulations including dimethyl-sulfoxide as explicit solvent have been carried out on the free MIR peptide. Calculation of the structure of the [A76]MIR analogue bound to an anti-MIR monoclonal antibody have been performed in the presence of water molecules. A tightly folded structure appears for both peptides with alpha beta-folded N-terminal N68-P-A-D71 sequence of type I in the free state and type III in the mAb6-bound state. The C-terminal sequence is folded in two different ways according to the result in the free and bound state of the peptides: two overlapping beta/beta or beta/alpha turns result in a short helical sequence in the free MIR peptide, whereas the bound analogue is folded by uncommon hydrogen bond closing an 11-membered cycle. This structural evolution is essentially the result of the reorientation of the hydrophobic side chains that are probably directly involved in peptide--antibody recognition.

Animals↗
PubMed2006

Construction of enzyme-substrate complexes between hen egg-white lysozyme and N-acetyl-D-glucosamine hexamer by systematic conformational search and molecular dynamics simulation.

We constructed the complexes between HEWL and (GlcNAc)6 oligomer in order to investigate the amino acid residues related to substrate binding in the productive and nonproductive complexes, and the relationship between the distortion of the GlcNAc residue D and the formation of the productive complexes. We obtained 49 HEWL-(GlcNAc)6 complexes by a systematic conformational search and classified the each one to the three binding modes; left side, center, or right side. Furthermore we performed the molecular dynamics simulation against 20 HEWL-(GlcNAc)6 complexes (8: chair model, 12 : half-chair model) selected from the 49 complexes to investigate the interaction between HEWL and (GlcNAc)6. As results, we confirmed that it is necessary for GlcNAc residue D to be half-chaired form to bind toward the right side to form productive complexes. We found newly that eight amino acid residues interact with the (GlcNAc)6 oligomer, as follows, Arg73, Gly102, Asn103 for GlcNAc residue A; Asn103 for GlcNAc residues B and C; Leu56, Ala107, Val109 for GlcNAc residue D; Ala110 for GlcNAc residue E; and Lys33 for GlcNAc residue F. We also indicated that GlcNAc residue F does not interact with Thr47 and rarely interacts with Phe34 and Asn37.

Acetylglucosamine↗
PubMed1995

Conformation of parathyroid hormone antagonists by CD, NMR, and molecular dynamics simulations.

The conformation of two highly potent parathyroid hormone (PTH) antagonists was investigated in water/2,2,2-trifluoroethanol mixtures. The two peptides are derived from the sequence (7-34) of PTH and of PTH-related protein (PTHrP) and have a D-Trp replacing Gly in position 12. In the analogue derived from PTHrP, Lys11 was replaced by Leu to remove the residual agonist activity. The study was conducted by CD and two-dimensional proton magnetic resonance spectroscopy, and the nuclear Overhauser effects found were utilized in restrained distance geometry and molecular dynamics simulations. Both peptides adopt a helical C-terminal conformation, which seems more stable in the case of the PTHrP analogue. A type II' beta-turn centered around D-Trp12 and Lys13 is present in both structures.

Amino Acid Sequence↗
PubMed2000

Characterization of the unfolding pathway of the cell-cycle protein p13suc1 by molecular dynamics simulations: implications for domain swapping.

BACKGROUND: The p13suc1 gene product is a member of the cks (cyclin-dependent protein kinase subunit) protein family and has been implicated in regulation of the cell cycle. Various crystal structures of suc1 are available, including a globular, monomeric form and a beta-strand exchanged dimer. It has been suggested that conversions between these forms, and perhaps others, may be important in the regulation of the cell cycle. RESULTS: We have undertaken molecular dynamics simulations of protein unfolding to investigate the conformational properties of suc1. Unfolding transition states were identified for each of four simulations. These states contain some native secondary structure, primarily helix alpha1 and the core of the beta sheet. The hydrophobic core is loosely packed. Further unfolding leads to an intermediate state that is slightly more expanded than the transition state, but with considerably fewer nonlocal, tertiary packing contacts and less secondary structure. The helices are fluctuating but partially formed in the denatured state and beta2 and beta4 remain associated. CONCLUSIONS: It appears that suc1 folds by a nucleation-condensation mechanism, similar to that observed for two-state folding proteins. However, suc1 forms an intermediate during unfolding and contains considerable residual structure in the denatured state. The stability of the beta2-beta4 residual structure is surprising, because beta4 is the strand involved in domain swapping. This stability suggests that the domain-swapping event, if physiologically relevant, may require the assistance of additional factors in vivo or occur early in the folding process.

Cell Cycle Proteins↗
PubMed2004

Conformational model of the Holliday junction transition deduced from molecular dynamics simulations.

Homologous recombination plays a key role in the restart of stalled replication forks and in the generation of genetic diversity. During this process, two homologous DNA molecules undergo strand exchange to form a four-way DNA (Holliday) junction. In the presence of metal ions, the Holliday junction folds into the stacked-X structure that has two alternative conformers. Experiments have revealed the spontaneous transitions between these conformers, but their detailed pathways are not known. Here, we report a series of molecular dynamics simulations of the Holliday junction at physiological and elevated (400 K) temperatures. The simulations reveal new tetrahedral intermediates and suggest a schematic framework for conformer transitions. The tetrahedral intermediates bear resemblance to the junction conformation in complex with a junction-resolving enzyme, T7 endonuclease I, and indeed, one intermediate forms a stable complex with the enzyme as demonstrated in one simulation. We also describe free energy minima for various states of the Holliday junction system, which arise during conformer transitions. The results show that magnesium ions stabilize the stacked-X form and destabilize the open and tetrahedral intermediates. Overall, our study provides a detailed dynamic model of the Holliday junction undergoing a conformer transition.

Computational Biology↗
PubMed2006

A combined molecular dynamics simulation and quantum chemical study on the mechanism for activation of the OxyR transcription factor by hydrogen peroxide.

Molecular dynamics (MD) simulations have been performed on the regulatory domain of the Escherichia coli OxyR transcription factor for the different chemical states along the mechanistic cycle for its activation by hydrogen peroxide. Conformational analysis indicates that His198 and Arg220 catalytic residues can be involved in the biochemical process of activation of OxyR. On the basis of the simulation data, a detailed mechanism for the oxidation process is suggested in which His198, in the presence of an arginine residue, functions as a unique acid-base catalyst in the successive oxidations of Cys199 and Cys208 by hydrogen peroxide. This mechanistic proposal has been tested by density functional theory (DFT-B3LYP) and ab initio (MP2) calculations on model systems. The two oxidations are both identified as nucleophilic substitution reactions of SN2 type with deprotonated cysteines functioning as nucleophiles. Both reactions have a calculated free energy of activation close to 15 kcal mol-1, which is consistent with the available experimental data on the kinetics of the activation process.

Amino Acids↗
PubMed2002

Molecular dynamics simulations of the ligand-binding domain of the ionotropic glutamate receptor GluR2.

Ionotropic glutamate receptors are essential for fast synaptic nerve transmission. Recent x-ray structures for the ligand-binding (S1S2) region of the GluR2 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive receptor have suggested how differences in protein/ligand interactions may determine whether a ligand will behave as a full agonist. We have used multiple molecular dynamics simulations of 2-5 ns duration to explore the structural dynamics of GluR2 S1S2 in the presence and absence of glutamate and in a complex with kainate. Our studies indicate that not only is the degree of domain closure dependent upon interactions with the ligand, but also that protein/ligand interactions influence the motion of the S2 domain with respect to S1. Differences in domain mobility between the three states (apo-S1S2, glutamate-bound, and kainate-bound) are surprisingly clear-cut. We discuss how these changes in dynamics may provide an explanation relating the mechanism of transmission of the agonist-binding event to channel opening. We also show here how the glutamate may adopt an alternative mode of binding not seen in the x-ray structure, which involves a key threonine (T480) side chain flipping into a new conformation. This new conformation results in an altered pattern of hydrogen bonding at the agonist-binding site.

Algorithms↗
PubMed2000

The role of side chains in the interaction of new antitumor pyrimidoacridinetriones with DNA: molecular dynamics simulations.

Pyrimidoacridinetriones (PATs) are a new group of highly active antitumor compounds. It seems reasonable to assume that, like for some other acridine derivatives, intercalation into DNA is a necessary, however not a sufficient condition for antitumor activity of these compounds. Rational design of new compounds of this chemotype requires knowledge about the structure of the intercalation complex, as well as about interactions responsible for its stability. Computer simulation techniques such as molecular dynamics (MD) may provide valuable information about these problems. The results of MD simulations performed for three rationally selected PATs are presented in this paper. The compounds differ in the number and position of side chains. Each of the compounds was simulated in two systems: i) in water, and ii) in the intercalation complex with the dodecamer duplex d(GCGCGCGCGCGC)2. The orientation of the side chain in relation to the ring system is determined by the position of its attachment. Orientation of the ring system inside the intercalation cavity depends on the number and position of side chain(s). The conformations of the side chain(s) of all PATs studied in the intercalation complex were found to be very similar to those observed in water.

Acridines↗
PubMed2005

Molecular dynamics simulations of GlpF in a micelle vs in a bilayer: conformational dynamics of a membrane protein as a function of environment.

Octyl glucoside (OG) is a detergent widely employed in structural and functional studies of membrane proteins. To better understand the nature of protein-OG interactions, molecular dynamics simulations (duration 10 ns) have been used to explore an alpha-helical membrane protein, GlpF, in OG micelles and in DMPC bilayers. Greater conformational drift of the extramembraneous protein loops, from the initial X-ray structure, is seen for the GlpF-OG simulations than for the GlpF-DMPC simulation. The mobility of the transmembrane alpha-helices is approximately 1.3x higher in the GlpF-OG than the GlpF-DMPC simulations. The detergent is seen to form an irregular torus around the protein. The presence of the protein leads to a small perturbation in the behavior of the alkyl chains in the OG micelle, namely an approximately 15% increase in the trans-gauche(-)-gauche(+) transition time. Aromatic side chains (Trp, Tyr) and basic side chains (Arg, Lys) play an important role in both protein-detergent (OG) and protein-lipid (DMPC) interactions.

Aquaporins↗
PubMed2002

Nanoseconds molecular dynamics simulation of primary mechanical energy transfer steps in F1-ATP synthase.

The mitochondrial membrane protein FoF1-ATP synthase synthesizes adenosine triphosphate (ATP), the universal currency of energy in the cell. This process involves mechanochemical energy transfer from a rotating asymmetric gamma-'stalk' to the three active sites of the F1 unit, which drives the bound ATP out of the binding pocket. Here, the primary structural changes associated with this energy transfer in F1-ATP synthase were studied with multi-nanosecond molecular dynamics simulations. By forced rotation of the gamma-stalk that mimics the effect of proton motive Fo-rotation during ATP synthesis, a time-resolved atomic model for the structural changes in the F1 part in terms of propagating conformational motions is obtained. For these, different time scales are found, which allows the separation of nanosecond from microsecond conformational motions. In the simulations, rotation of the gamma-stalk lowers the ATP affinity of the betaTP binding pocket and triggers fast, spontaneous closure of the empty betaE subunit. The simulations explain several mutation studies and the reduced hydrolysis rate of gamma-depleted F1-ATPase.

Adenosine Triphosphate↗
PubMed2005

Molecular dynamics simulation study on the transient response of solvation structure during the translational diffusion of solute.

The transient response function of the density profile of the solvent around a solute during the translational diffusion of the solute is formulated based on the generalized Langevin formalism. The resultant theory is applied to both neat Lennard-Jones fluids and cations in liquid water, and the response functions are obtained from the analysis of the molecular dynamics simulations. In the case of the self-diffusion of Lennard-Jones fluids, the responses of the solvation structures are in harmony with conventional pictures based on the mode-coupling theory, that is, the binary collision in the low-density fluids, the backflow effect from medium to high density fluids, and the backscatter effect in the liquids near the triple point. In the case of cations in water, the qualitative behavior is strongly dependent on the size of cations. The pictures similar to simple dense liquids are obtained for the large ion and the neutral molecule, while the solvent waters within the first solvation shell of small ions show an oscillatory response in the short-time region. In particular, the oscillation is remarkably underdumped for lithium ion. The origin of the oscillation is discussed in relation to the theoretical treatment of the translational diffusion of ions in water.

Journal Article↗
PubMed2003

Molecular dynamics simulation studies of cytochrome b5 from outer mitochondrial and microsomal membrane.

Two forms of cytochrome b(5) have been identified, associated with the outer membrane of liver mitochondria (OM cyt b(5)) and with the membrane of the endoplasmic reticulum (microsomal, Mc cyt b(5)). These proteins have very similar structures, but differ significantly in physical properties, with the OM cyt b(5) exhibiting a more negative reduction potential, higher stability, and stronger interactions with the heme. We perform molecular dynamics simulations to probe the structures and fluctuations of the two proteins in solution, to help explain the observed physical differences. We find that the structures of the two proteins, highly similar in the crystal, differ in position of a surface loop involving residues 49-51 in solution. Hydrophobic residues Ala-18, Ile-32, Leu-36, and Leu-47 tend to cluster together on the surface of rat OM cyt b(5), blocking water access to the protein interior. In bovine Mc cyt b(5), two of these positions, Ser-18 and Arg-47, are occupied by hydrophilic residues. This leads to breaking the hydrophobic cluster and allowing the protein to occupy a more open conformation. A measure of this structural transition is the opening of a cleft on the protein surface, which is 5 A wider in the OM cyt b(5) simulation compared to the Mc form. The OM protein also appears to have a more compact hydrophobic core in its beta-sheet region. These effects may be used to explain observed stability differences between the two proteins.

Amino Acid Sequence↗
PubMed2005

Conformational dynamics of the ligand-binding domain of inward rectifier K channels as revealed by molecular dynamics simulations: toward an understanding of Kir channel gating.

Inward rectifier (Kir) potassium channels are characterized by two transmembrane helices per subunit, plus an intracellular C-terminal domain that controls channel gating in response to changes in concentration of various ligands. Based on the crystal structure of the tetrameric C-terminal domain of Kir3.1, it is possible to build a homology model of the ATP-binding C-terminal domain of Kir6.2. Molecular dynamics simulations have been used to probe the dynamics of Kir C-terminal domains and to explore the relationship between their dynamics and possible mechanisms of channel gating. Multiple simulations, each of 10 ns duration, have been performed for Kir3.1 (crystal structure) and Kir6.2 (homology model), in both their monomeric and tetrameric forms. The Kir6.2 simulations were performed with and without bound ATP. The results of the simulations reveal comparable conformational stability for the crystal structure and the homology model. There is some decrease in conformational flexibility when comparing the monomers with the tetramers, corresponding mainly to the subunit interfaces in the tetramer. The beta-phosphate of ATP interacts with the side chain of K185 in the Kir6.2 model and simulations. The flexibility of the Kir6.2 tetramer is not changed greatly by the presence of bound ATP, other than in two loop regions. Principal components analysis of the simulated dynamics suggests loss of symmetry in both the Kir3.1 and Kir6.2 tetramers, consistent with "dimer-of-dimers" motion of subunits in C-terminal domains of the corresponding Kir channels. This is suggestive of a gating model in which a transition between exact tetrameric symmetry and dimer-of-dimers symmetry is associated with a change in transmembrane helix packing coupled to gating of the channel. Dimer-of-dimers motion of the C-terminal domain tetramer is also supported by coarse-grained (anisotropic network model) calculations. It is of interest that loss of exact rotational symmetry has also been suggested to play a role in gating in the bacterial Kir homolog, KirBac1.1, and in the nicotinic acetylcholine receptor channel.

Adenosine Triphosphate↗
PubMed2004

Equation of state of a seven-dimensional hard-sphere fluid. Percus-Yevick theory and molecular-dynamics simulations.

Following the work of Leutheusser [Physica A 127, 667 (1984)], the solution to the Percus-Yevick equation for a seven-dimensional hard-sphere fluid is explicitly found. This allows the derivation of the equation of state for the fluid taking both the virial and the compressibility routes. An analysis of the virial coefficients and the determination of the radius of convergence of the virial series are carried out. Molecular-dynamics simulations of the same system are also performed and a comparison between the simulation results for the compressibility factor and theoretical expressions for the same quantity is presented.

Journal Article↗
PubMed2002

Molecular dynamics simulations of a hydrated protein vectorially oriented on polar and nonpolar soft surfaces.

We present a collection of molecular dynamics computer simulation studies on a model protein-membrane system, namely a cytochrome c monolayer attached to an organic self-assembled monolayer (SAM). Modifications of the system are explored, including the polarity of the SAM endgroups, the amount of water present for hydration, and the coordination number of the heme iron atom. Various structural parameters are measured, e.g., the protein radius of gyration and eccentricity, the deviation of the protein backbone from the x-ray crystal structure, the orientation of the protein relative to the SAM surface, and the profile structures of the SAM, protein, and water. The polar SAM appears to interact more strongly with the protein than does the nonpolar SAM. Increased hydration of the system tends to reduce the effects of other parameters. The choice of iron coordination model has a significant effect on the protein structure and the heme orientation. The overall protein structure is largely conserved, except at each end of the sequence and in one loop region. The SAM structure is only perturbed in the region of its direct contact with the protein. Our calculations are in reasonably good agreement with experimental measurements (polarized optical absorption/emission spectroscopy, x-ray interferometry, and neutron interferometry).

Binding Sites↗
PubMed1993

Tri- and diglycine backbone rotational dynamics investigated by 13C NMR multiplet relaxation and molecular dynamics simulations.

Backbone motional dynamics in tri- and diglycine have been investigated by using 13C NMR multiplet relaxation spectroscopy. Dipolar auto- and cross-correlation times were determined as a function of pH, ionic strength, and temperature. Molecular dynamics simulations and phi,psi bond rotation energy profiles were calculated for insight into the physical nature of backbone rotations that could contribute to 13C relaxation. Various motional models were used to fit the experimental data. For internal glycine G2 in triglycine, restricted and unrestricted rotational diffusion models both underestimate internal correlation times, although they do agree that the axis of fastest internal rotation is directed closely along the C alpha-C bond. For di- and triglycine, significant pH dependencies in cross-correlation times for C-terminal glycines, and more so for those of N-terminal glycines, indicate the importance of the ionization state in internal mobility of terminal backbone positions. For terminal glycines, rotational jump models which allow for diffusive-like fluctuations within minima best explain the experimental data. phi,psi rotational fluctuation amplitudes and internal rotational energy barriers derived from the temperature dependence of 13C relaxation parameters, which range from 3 to 5 kcal/mol, agree well with those values calculated in rotational energy profiles.

Amino Acid Sequence↗
PubMed1990

Three-dimensional model and molecular dynamics simulation of the active site of the self-splicing intervening sequence of the bacteriophage T4 nrdB messenger RNA.

The secondary and 3D structure of the active site of the self-splicing T4 nrdB RNA has been modeled on a graphics workstation by use of the suggested 3D arrangement of the active site of the Tetrahymena IVS [Kim, S.H., & Cech, T.R. (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 8788-8792] as a guideline. The initially obtained crude structure was then subjected to molecular mechanics energy minimization and molecular dynamics simulation to relax tensions. In this process the energy decreased considerably and gave a final structure that deviated by 3 A [root mean square (rms)] from the initial structure. The cofactor guanosine (and the competitive inhibitor arginine) was docked to a proposed [Michel, F., Hanna, M., Green, R., Bartel, D.P., & Szostak, J.W. (1989) Nature 342, 391-395] binding site, where it was found to fit rather well. A minor modification of the binding mode easily brought the O3' end of the guanosine within 2 A of the phosphodiester bond where the primary cleavage occurs.

Animals↗
PubMed2000

Homology modeling and molecular dynamics simulation studies of an inward rectifier potassium channel.

A homology model has been generated for the pore-forming domain of Kir6.2, a component of an ATP-sensitive K channel, based on the x-ray structure of the bacterial channel KcsA. Analysis of the lipid-exposed and pore-lining surfaces of the model reveals them to be compatible with the known features of membrane proteins and Kir channels, respectively. The Kir6.2 homology model was used as the starting point for nanosecond-duration molecular dynamics simulations in a solvated phospholipid bilayer. The overall drift from the model structure was comparable to that seen for KcsA in previous similar simulations. Preliminary analysis of the interactions of the Kir6.2 channel model with K(+) ions and water molecules during these simulations suggests that concerted single-file motion of K(+) ions and water through the selectivity filter occurs. This is similar to such motion observed in simulations of KcsA. This suggests that a single-filing mechanism is conserved between different K channel structures and may be robust to changes in simulation details. Comparison of Kir6.2 and KcsA suggests some degree of flexibility in the filter, thus complicating models of ion selectivity based upon a rigid filter.

Amino Acid Sequence↗