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PubMed1989

Superoxide dismutase: fluctuations in the structure and solvation of the active site channel studied by molecular dynamics simulation.

The molecular dynamics (MD) simulation of superoxide dismutase (SOD) in water is carried out for a total of 23 ps. The simulation system is a 26 A sphere centered at the active site of SOD, including 1602 atoms from SOD and 1761 water molecules. There is no gross deviation from the x-ray structure for the average MD structure. The structure and potential fluctuations around the active site are examined. The results provide new insight to the interactions between SOD and its substrate superoxide.

Binding Sites↗
PubMed1999

Structural and dynamic differences of the estrogen receptor DNA-binding domain, binding as a dimer and as a monomer to DNA: molecular dynamics simulation studies.

Molecular dynamics (MD) simulations of the estrogen receptor DNA-binding domain (ERDBD) as a dimer in complex with its DNA response element (ERE) show a significant difference in both structure and dynamics, compared to a MD simulation of monomeric ERDBD bound to its half-site response element (EREH). The C-terminal zinc binding domain (ZnII), including a region (helix II) which is in a helical conformation in ERE-(ERDBD)2, is considerably more flexible in EREH-ERDBD than in the dimeric complex. In EREH-ERDBD, all helical hydrogen bonds in helix II are broken and the entire ZnII region is detached from a hydrogen bonding network that in ERE-(ERDBD)2 connects to other parts of the protein as well as to the DNA. The regions that become flexible in EREH-ERDBD are identical to the regions where the NMR solution structure of free ERDBD is poorly ordered. This strongly suggests that dimerisation of ERDBD is required for ordering of the ZnII region and that monomeric binding to DNA is not sufficient for the ordering. This contrasts to the glucocorticoid receptor DNA-binding domain (GRDBD) which has essentially the same mobility (uniform and limited), regardless of whether it is free as a monomer in solution, bound as a monomer to its half-site response element or in a dimeric complex with the full response element. The hydrogen bonding network that connects ZnII with other parts of the protein and to DNA is almost identical in ERDBD and GRDBD. However, in GRDBD there is also a serine (in the N-terminal zinc coordinating region) with a central role in this network, connecting to the ZnII region. This serine is replaced by a glycine in ERDBD and we suggest that this substitution is sufficient for destabilisation of the network, thus leading to a more flexible ZnII region, which becomes ordered first upon forming a complex with another ERDBD and DNA.

Amino Acid Sequence↗
PubMed1996

H-bond stability in the tRNA(Asp) anticodon hairpin: 3 ns of multiple molecular dynamics simulations.

Multiple molecular dynamics trajectories of the solvated and neutralized 17-residue tRNA(Asp) anticodon hairpin were generated for a total of 3 ns. Explicit treatment of all long-ranged electrostatic interactions by the particle mesh Ewald algorithm, as implemented in the AMBER MD software package, effected a degree of structural stabilization not previously achieved by use of a long 16-A solvent interaction truncation scheme. The increased stability of this multiple molecular dynamics set was appropriate for an in-depth analysis of the six 500-ps-long trajectories and allowed the characterization of a number of key structural interactions. The dynamical behavior of the standard Watson-Crick base pairs, the noncanonical G30-U40 "wobble" base pair, and the psi 32-C38 pseudo-base pair is presented as well as that of two C--H... O hydrogen bonds found to contribute to the array of tertiary interactions that stabilize the seven-nucleotide native loop conformation. The least mobile residue in the loop is U33, which forms the U-turn motif and which participates in several hydrogen-bonding interactions, whereas the most mobile residue is the apical residue G34 at the wobble position, a factor undoubtedly important in its biological function. The set of multiple molecular dynamics trajectories obtained does not converge on a 500-ps time scale to a unique dynamical model but instead describes an ensemble of structural microstates accessible to the system under the present simulation protocol, which is the result of local structural heterogeneity rather than of global conformational changes.

Anticodon↗
PubMed1996

Understanding water: molecular dynamics simulations of myoglobin.

Molecular dynamics simulations were performed on CO myoglobin to evaluate the stability of the bound water molecules as determined in a neutron diffraction analysis. The myoglobin structure derived from the neutron analysis provided the starting coordinate set used in the simulation. The simulations show that only a few water molecules are tightly bound to protein atoms, while most solvent molecules are labile, breaking and reforming hydrogen bonds. Comparison between myoglobin in solution and in a single crystal highlighted some of the packing effects on the solvent structure and shows that water solvent plays an indispensable role in protein dynamics and structural stability. The described observations explain some of the differences in the experimental results of protein hydration as observed in NMR, neutron and X-ray diffraction studies.

Computer Simulation↗
PubMedDate not supplied

Disaccharide conformational flexibility. II. Molecular dynamics simulations of sucrose.

Molecular dynamics simulations have been used to study the motions in vacuum of the disaccharide sucrose. Ensembles of trajectories were calculated for each of the five local minimum energy conformations identified in the adiabatic conformational energy mapping of this molecule. The model sucrose molecules were found to exhibit a variety of motions, although the global minimum energy conformation was found to be dynamically stable, and no transitions away from this structure were observed to occur spontaneously. In all but one of these vacuum trajectories, the intramolecular hydrogen bond between residues was maintained, in accord with recent nmr studies of this molecule in aqueous solution. Considerable flexibility of the furanoid ring was found in the trajectories. No "flips" to the opposite puckering for this ring were found in the simulations starting from the global minimum, although such a transition was observed for a trajectory initiated with one of the higher local minimum energy conformations. Overall, the observed structural fluctuations were consistent with the experimental picture of sucrose as a relatively rigid molecule.

Carbohydrate Conformation↗
PubMed1998

Plasticity induced by shock waves in nonequilibrium molecular-dynamics simulations

Nonequilibrium molecular-dynamics simulations of shock waves in three-dimensional 10-million atom face-centered cubic crystals with cross-sectional dimensions of 100 by 100 unit cells show that the system slips along all of the available 111 slip planes, in different places along the nonplanar shock front. Comparison of these simulations with earlier ones on a smaller scale not only eliminates the possibility that the observed slippage is an artifact of transverse periodic boundary conditions, but also reveals the richness of the nanostructure left behind. By introducing a piston face that is no longer perfectly flat, mimicking a line or surface inhomogeneity in the unshocked material, it is shown that for weaker shock waves (below the perfect-crystal yield strength), stacking faults can be nucleated by preexisting extended defects.

Journal Article↗
PubMed1985

Atomic motions in phenylalanine transfer RNA probed by molecular dynamics simulations.

A 24 psec molecular dynamics simulation of tRNAPhe reveals a very stable model whose average structure is close to that of the crystallographic studies. The root mean square atomic motions correlate very well with the thermal factors from crystallography and are largely determined by packing forces. These motions are generally more anisotropic than those seen in a molecular dynamics simulation of a globular protein, and the anisotropic effects are also primarily a consequence of packing considerations. The development and examination of molecular dynamics models for macromolecules is an interesting basic research problem in biophysical chemistry, and it is now reasonably well advanced. The more exciting tasks of using these models to predict experimental properties and to examine biological function are just beginning.

Models, Molecular↗
PubMed1994

Investigation of shape variations in the antibody binding site by molecular dynamics computer simulation.

Molecular dynamics simulations have been used to investigate the flexibility and variations in the shape of the binding site of an antibody against human Rhinovirus serotype 2 (HRV2) and its complex with a 15 amino acid oligopeptide, the structure of which has been recently determined by X-ray crystallography. During the simulation of the unbound antibody the binding site, defined in terms of the hypervariable regions or complementarity determining regions (CDRs), shows significant fluctuations in shape. For the complex such variations in the shape of the binding site were reduced. The largest fluctuations in the unbound antibody occurred within the CDR-H3. The largest differences between the bound and unbound crystal structures are also associated with CDR-H3. The relative displacements of the loops have been analysed in terms of internal distortions, rigid body motions of the loops and changes with respect to the framework regions. The degree to which the motions of the loops are correlated and the variation in the volume of the binding pocket during the simulation have also been examined.

Amino Acid Sequence↗
PubMed1990

Molecular dynamics simulations in biology.

Molecular dynamics--the science of simulating the motions of a system of particles--applied to biological macromolecules gives the fluctuations in the relative positions of the atoms in a protein or in DNA as a function of time. Knowledge of these motions provides insights into biological phenomena such as the role of flexibility in ligand binding and the rapid solvation of the electron transfer state in photosynthesis. Molecular dynamics is also being used to determine protein structures from NMR, to refine protein X-ray crystal structures faster from poorer starting models, and to calculate the free energy changes resulting from mutations in proteins.

Chemical Phenomena↗
PubMed1998

Ab initio modeling and molecular dynamics simulation of the alpha 1b-adrenergic receptor activation.

This work describes the ab initio procedure employed to build an activation model for the alpha 1b-adrenergic receptor (alpha 1b-AR). The first version of the model was progressively modified and complicated by means of a many-step iterative procedure characterized by the employment of experimental validations of the model in each upgrading step. A combined simulated (molecular dynamics) and experimental mutagenesis approach was used to determine the structural and dynamic features characterizing the inactive and active states of alpha 1b-AR. The latest version of the model has been successfully challenged with respect to its ability to interpret and predict the functional properties of a large number of mutants. The iterative approach employed to describe alpha 1b-AR activation in terms of molecular structure and dynamics allows further complications of the model to allow prediction and interpretation of an ever-increasing number of experimental data.

Amino Acid Sequence↗
PubMed1992

Application of restrained minimization, simulated annealing and molecular dynamics simulations for the conformational analysis of oligosaccharides.

The purpose of the present study was to determine the confidence with which the small number of 1H NMR nuclear Overhauser effect (NOE) distance constraints measurable across glycosidic linkages in oligosaccharides could be used for solution conformational analysis. This was assessed by use of these constraints in restrained molecular mechanical minimization of the tetrasaccharide Gal beta 1----4(Fuc alpha 1----3)Glc-NAc beta 1----3Gal, a model compound of the Lewis-X antigenic determinant. This presents a particularly severe test case in view of extreme resonance overlap and a dearth of inter-residue distance constraints. It is concluded that these constraints, when used in conventional restrained minimization, result in the generation of 'virtual conformations' and local minima about glycosidic linkages. However, these restraints are nevertheless found to be useful in the initial stages of a conformational analysis strategy involving restrained minimization combined with dynamical simulated annealing to define more accurately the global minimum energy configuration, together with molecular dynamics simulation to explore conformational mobility about this minimum. Theoretical ROE values calculated over the time course of the MD simulation, using a formalism appropriate for the time scale of the internal motion, are compared with those obtained experimentally in the oligosaccharide.

Carbohydrate Conformation↗
PubMed1998

Locally accessible conformations of proteins: multiple molecular dynamics simulations of crambin.

Multiple molecular dynamics (MD) simulations of crambin with different initial atomic velocities are used to sample conformations in the vicinity of the native structure. Individual trajectories of length up to 5 ns sample only a fraction of the conformational distribution generated by ten independent 120 ps trajectories at 300 K. The backbone atom conformational space distribution is analyzed using principal components analysis (PCA). Four different major conformational regions are found. In general, a trajectory samples only one region and few transitions between the regions are observed. Consequently, the averages of structural and dynamic properties over the ten trajectories differ significantly from those obtained from individual trajectories. The nature of the conformational sampling has important consequences for the utilization of MD simulations for a wide range of problems, such as comparisons with X-ray or NMR data. The overall average structure is significantly closer to the X-ray structure than any of the individual trajectory average structures. The high frequency (less than 10 ps) atomic fluctuations from the ten trajectories tend to be similar, but the lower frequency (100 ps) motions are different. To improve conformational sampling in molecular dynamics simulations of proteins, as in nucleic acids, multiple trajectories with different initial conditions should be used rather than a single long trajectory.

Computer Simulation↗
PubMed1998

Non-native interactions in protein folding intermediates: molecular dynamics simulations of hen lysozyme.

Molecular dynamics simulations of protein denaturation can complement and extend experimental studies of protein folding by providing atomic-level structural information about conformational transitions and any conformational states along the unfolding pathway. Previous unfolding simulations of hen egg-white lysozyme have resulted in intermediate structures with an unfolded alpha-domain and a structured beta-domain, which is inconsistent with experiment. In contrast, the beta-domain unfolded first in the two simulations presented here leaving a structured alpha-domain. Following this, intermediate states were identified that differ with respect to the packing of the helices and the elements of non-native structure adopted. The non-native structure is critical for explaining many of the experimental observations. Overall, the pooled ensemble of these intermediates is in agreement with the experimental data for the major kinetic intermediate, suggesting that the kinetic intermediate may be made up of distinct, but rapidly interconverting, partially folded conformations distinguished primarily by differences in helix packing.

Amino Acid Sequence↗
PubMed1992

Characterization of "native" apomyoglobin by molecular dynamics simulation.

We have used molecular dynamics simulation methods to study the structure and fluctuations of "native" apomyoglobin in aqueous solution for a period of greater than 0.5 nanosecond. This work was motivated by the recent attempts of Hughson et al. to characterize the structure and motion of both this molecule and the less compact, acid stabilized I stage, using methods of pulsed H/2H exchange. The study of these systems provides new insights into protein folding intermediates and our simulation has yielded a detailed model for structure and fluctuations in apomyoglobin which complements the experimental studies. We find that local (short-time) fluctuations agree well with fluctuations observed for the holoprotein in aqueous solution, as well as results from the crystallographic B-factors. In addition, the structural features we observe for native apomyoglobin are very similar to the holoprotein, in basic agreement with the findings of Hughson et al. By examining larger-scale motions, developing only over timescales in excess of a 100 picoseconds, we are able to identify conformationally "labile" and "non-labile" regions within native apomyoglobin. These regions correspond extremely well to those identified in the nuclear magnetic resonance experiments as unstable and stable "folding subdomains" in the I state of apomyoglobin. Overall we find that helices A, B, E, G and H show the least amount of motion and helices C, D and F move substantially over the timescales examined. The major motions, and the primary difference between the holo and apo structures as we have observed them, are due to the shifting motion of helices C, D and F into the vacant heme cavity. We also find that motions at the interface of helical segments can be large, with one important exception being the chain segment connecting helices G and H. This segment of chain interacts with the conformationally "non-labile" helix A to form a relatively rigid subdomain composed of helices A, G and H. We believe that these findings provide direct support for the suggestion of Hughson et al. that helices A, G and H constitute a compact subdomain that remains in a native-like conformation as the protein begins to unfold in environments of decreasing pH.

Apoproteins↗
PubMed1993

Dynamical properties of bovine pancreatic trypsin inhibitor from a molecular dynamics simulation at 5000 atm.

Molecular dynamics simulations of bovine pancreatic trypsin inhibitor in water have been performed with coupling to pressure baths at 1 atm and at 5000 atm. The positional fluctuations of atoms in the alpha- and gamma-positions are slightly decreased at 5000 atm. The mobility of the backbone phi- and psi-angles is not affected with respect to the root mean square fluctuations and the rate of torsional angle transitions. The amplitude of libration of sidechain chi-angles remains nearly the same for both pressures, but the rate of torsional angle transitions decreases on average by 30% when increasing the hydrostatic pressure to 5000 atm.

Amino Acid Sequence↗
PubMed1995

Rigid-body motions of sub-units in DNA: a correlation analysis of a 200 ps molecular dynamics simulation.

A 200 ps molecular dynamics simulation of the B-form double stranded self-complementary octanucleotide d(CTGATCAG) is analyzed in terms of correlated motions using the canonical analysis approach. Each nucleotide is decomposed in three sub-units corresponding to the base, the sugar ring and the backbone respectively. The correlation between the full dynamics of two sub-units was found to decrease as their mutual distance increases. The interpretation of the full dynamics of sub-units as the superimposition of rigid-body motions (translation and orientation) and deformation shows that the main source of correlation is rigid-body motions. Correlation between sub-units deformation is weak and practically vanishes for sub-units belonging to non-adjacent nucleotides. It is also shown that the correlation is much more important for sub-units of the same strand than of opposite strands. We conclude that the internal dynamics of the octanucleotide may be well described by rigid-body motions, the sub-units deformation having only local influence whereas sub-units translation and rotation have repercussion to long distances. The results presented in this study suggest how the number of degrees of freedom may be reduced for simulating long-time dynamics of oligonucleotides.

Computer Simulation↗
PubMed1994

Molecular dynamics simulations of phospholipid bilayers.

Molecular dynamics (MD) simulations at 37 degrees C have been performed on three phospholipid bilayer systems composed of the lipids DLPE, DOPE, and DOPC. The model used included 24 explicit lipid molecules and explicit waters of solvation in the polar head group regions, together with constant-pressure periodic boundary conditions in three dimensions. Using this model, a MD simulation samples part of an infinite planar lipid bilayer. The lipid dynamics and packing behavior were characterized. Furthermore, using the results of the simulations, a number of diverse properties including bilayer structural parameters, hydrocarbon chain order parameters, dihedral conformations, electron density profile, hydration per lipid, and water distribution along the bilayer normal were calculated. Many of these properties are available for the three lipid systems chosen, making them well suited for evaluating the model and protocols used in these simulations by direct comparisons with experimental data. The calculated MD behavior, chain disorder, and lipid packing parameter, i.e. the ratio of the effective areas of hydrocarbon tails and head group per lipid (a(t)/ah), correctly predict the aggregation preferences of the three lipids observed experimentally at 37 degrees C, namely: a gel bilayer for DLPE, a hexagonal tube for DOPE, and a liquid crystalline bilayer for DOPC. In addition, the model and conditions used in the MD simulations led to good agreement of the calculated properties of the bilayers with available experimental results, demonstrating the reliability of the simulations. The effects of the cis unsaturation in the hydrocarbon chains of DOPE and DOPC, compared to the fully saturated one in DLPE, as well as the effects of the different polar head groups of PC and PE with the same unsaturated chains on the lipid packing and bilayer structure have been investigated. The results of these studies indicate the ability of MD methods to provide molecular-level insights into the structure and dynamics of lipid assemblies.

Algorithms↗
PubMed1995

Structure, thermodynamics and cooperativity of the glucocorticoid receptor DNA-binding domain in complex with different response elements. Molecular dynamics simulation and free energy perturbation studies.

Molecular dynamics simulations and free energy perturbation calculations have been performed on the glucocorticoid receptor DNA-binding domain (GRDBD) in complex with three different half-site response elements (RE). These are the glucocorticoid receptor RE (GREH), the estrogen receptor RE (EREH) and an "intermediate" RE (GRE2H), where the base-pair 6A.T in GREH has been replaced by 6G.C. The molecular dynamics/free energy perturbation calculations reveal the same order of stability of the three complexes, i.e. GREH-GRDBD > GRE2H-GRDBD > EREH-GRDBD, as found experimentally, with reasonable quantitative agreement of the relative stabilities with the experiments. The more favourable entropy in associating GRDBD to GREH than to GRE2H could be explained by the additional non-polar surface that is removed from the solvent in the former complex formation. Part of this additional surface originates from the 6T methyl group in GREH. Sequence-dependent hydration patterns of the DNA major groove, which is interrupted by the GRDBD binding, could also contribute to the relatively more favourable entropy in forming GREH-GRDBD than GRE2H-GRDBD. The tenfold reduced cooperativity in the dimeric GRDBD binding to a partially palindromic ERE (palERE) compared to palGRE/GRE2 could be attributed to conformational changes in the residues of the "D-box" (Cys476 to Cys482) observed in the molecular dynamics simulations of EREH-GRDBD, but not in the other two complexes. Moreover, the conformations of the base-pairs at positions 5 and 6 are distorted (compared to free B-DNA) in GREH and GRE2H, due to the binding of GRDBD. Since the corresponding conformational distortions were not found in EREH-GRDBD, it is plausible that the distortions mediate cooperative binding through a propagation of the distortions to the other half site, thus facilitating binding of the second GRDBD.

Amino Acid Sequence↗