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PubMed2001

Molecular dynamics simulation of Escherichia coli dihydrofolate reductase and its protein fragments: relative stabilities in experiment and simulations.

We have carried out molecular dynamics simulations of the native dihydrofolate reductase from Escherichia coli and several of its folded protein fragments at standard temperature. The simulations have shown fragments 1--36, 37--88, and 89--159 to be unstable, with a C(alpha)RMSD (C(alpha) root mean squared deviation) >5 A after 3.0 nsec of simulation. The unfolding of fragment 1--36 was immediate, whereas fragments 37--88 and 89--159 gradually unfolded because of the presence of the beta-sheet core structure. In the absence of residues 1--36, the two distinct domains comprising fragment 39--159 associated with each other, resulting in a stable conformation. This conformation retained most of its native structural elements. We have further simulated fragments derived from computational protein cutting. These were also found to be unstable, with the exception of fragment 104--159. In the absence of alpha(4), the loose loop region of residues 120--127 exhibited a beta-strand-like behavior, associating itself with the beta-sheet core of the protein fragment. The current study suggests that the folding of dihydrofolate reductase involves cooperative folding of distinct domains which otherwise would have been unstable as independent folded units in solution. Finally, the critical role of residues 1--36 in allowing the two distinct domains of fragment 104--159 to fold into the final native conformation is discussed.

Computer Simulation↗

PubMed2005

Vibrational study of a molecular device using molecular dynamics simulations.

A Potential scenario for the implementation of molecular electronic systems is introduced by applying digital signal processing techniques to results from classical molecular dynamics simulations of a molecular system interconnected by nanosize gold clusters. Under this new scenario, signals can be introduced, processed, and read through interactions with the internal vibrational modes of the small molecular unit. We use modulation operations intrinsically inherent to any molecular system as a concept proof. As an example of this type of analysis, we focus on the individual oscillations between C-H and C-C bonds and cluster-cluster displacements.

Carbon↗

PubMed2004

A conformational study of alpha-D-Manp-(1-->2)-alpha-D-Manp-(1-->O)-L-Ser by NMR 1H,1H T-ROESY experiments and molecular-dynamics simulations.

The conformational preference of alpha-D-Manp-(1-->2)-alpha-D-Manp-(1-->O)-L-Ser has been investigated by one-dimensional (1)H,(1)H T-ROESY experiments and molecular-dynamics simulations with CHARMM22 type of force fields and water as explicit solvent. Proton-proton distances were obtained from the simulations and subsequently experimentally determined distances could be derived. Measurements were performed on the title compound as well as on selectively deuterium-substituted analogues synthesized as part of this study to alleviate possible NMR spectroscopic difficulties. A very good agreement was present between the separate NMR experiments. In the subsequent analysis a key nuclear Overhauser effect between the anomeric protons in the two sugar residues was used to assess the conformational dynamics revealed by the molecular simulations. The combined results support a model in which two states are significantly populated as a result of flexibility around the bond defined by the glycosidic torsion angle psi.

Carbohydrate Conformation↗

PubMed2001

Dynamic structures of horse liver alcohol dehydrogenase (HLADH): results of molecular dynamics simulations of HLADH-NAD(+)-PhCH(2)OH, HLADH-NAD(+)-PhCH(2)O(-), and HLADH-NADH-PhCHO.

Molecular dynamics simulations of the oxidation of benzyl alcohol by horse liver alcohol dehydrogenase (HLADH) have been carried out. The following three states have been studied: HLADH.PhCH(2)OH.NAD(+) (MD1), HLADH.PhCH(2)O(-).NAD(+) (MD2), and HLADH.PhCHO.NADH (MD3). MD1, MD2, and MD3 simulations were carried out on one of the subunits of the dimeric enzyme covered in a 32-A-radius sphere of TIP3P water centered on the active site. The proton produced on ionization of the alcohol when HLADH.PhCH(2)OH.NAD(+) --> HLADH.PhCH(2)O(-).NAD(+) is transferred from the active site to solvent water via a hydrogen bonding network consisting of serine48 hydroxyl, ribose 2'- and 3'-hydroxyl groups, and Hist51. Hydrogen bonding of the 3'OH of ribose to Ile269 carbonyl maintains this proton in position to be transferred to water. Molecular dynamic simulations have been employed to track water1287 from the TIP3 water pool to the active site, thus exhibiting the mode of entrance of water to the active site. With time the water1287 accumulates in two different positions in order to accept the proton from the ribose 3'-OH and from His51. There can be identified two structural substates for proton passage. In the first substate the imidazole Ne2 of His51 is adjacent to the nicotinamide ribose C2'-OH and hydrogen bonding distances for proton transfer through the hydrogen bonded relay series PhCH(2)OH...Ser48-OH...Ribose2'-OH...His51...OH(2) (path 1) average 2.0, 2.0, and 2.1 A and (for His51...OH(2)) minimal distances less or equal to 2.5 A. The structure for path 1 is present 20% of the time span. And in the second substate, there are two possible proton passages: path 1 as before and path 2. Path 2 involves the hydrogen-bonded relay series PhCH(2)OH...Ser48-OH...Ribose2'-OH...Ribose3'-OH...His51.OH(2) with the average bonding distances being 2.0, 2.0, 2.1, and 2.0 A and (for His51...OH(2)) minimal distances less or equal to 2.5 A (20% probability of the time span), respectively. During the molecular dynamics simulation the NAD(+) ribose conformations have stabilized at the C2'-endo-C3'-exo or the C2'-endo conformations. With the C2'-endo conformation the first and second substates are able to persist for different time spans, while with the C2'-endo-C3'-exo conformation the only possible pathway involves the first substate. For both first and second substates the fluctuation of the distances between the ribose-OH protons and N epsilon 2 of His51 imidazole ring is partially contributed by the "windshield wiper" motion of the His51 imidazole ring. Since the imidazole of His-51 contributes only about 10-fold to activity, as estimated from the decrease in activity upon substitution with a Gln, there must be an alternate route for the proton to pass to solvent without going through this histidine. A third pathway involves ribose C3'-OH and Ile-269. In MD2, near attack conformers (NACs) for hydride transfer from PhCH(2)O(-) to NAD(+) represent approximately 60% of E.S conformers. The molecular dynamic study of MD3 at mildly basic pH reveals that reactive ground state conformers (NACs) for hydride transfer from NADH to PhCHO amount to 12 mol % of conformers. In MD3, anisotropic bending of the dihydronicotinamide ring of NADH (average value of alpha(c) = 4.0 degrees and alpha(n) = 0.5 degrees, respectively) is observed.

Alcohol Dehydrogenase↗

PubMed2002

Molecular dynamics simulation of a DNA containing a single strand break.

Molecular dynamics simulations were performed for a dodecamer DNA containing a single strand break (SSB), which has been represented by a 3'-OH deoxyribose and 5'-OH phosphate in the middle of the strand. Molecular force field parameters of the 5'-OH phosphate region were determined from an ab initio calculation at the HF/6-31G level using the program package GAMESS. The DNA was placed in a periodic boundary box with water molecules and Na+ counter-ions to produce a neutralised system. After minimisation, the system was heated to 300 K, equilibrated and a production run at constant NTP was executed for 1 ns using AMBER 4.1. Snapshots of the SSB-containing DNA and a detailed analysis of the equilibrated average structure revealed surprisingly small conformational changes compared to normal DNA. However, dynamic properties calculated using the essential dynamics method showed some features that may be important for the recognition of this damage by repair enzymes.

Base Pairing↗

PubMed1998

Molecular dynamics simulation of colchicinoids.

Colchicine, a tricyclic alkaloid, has a remarkable range of biological activities. It binds with tubulin and prevents the formation of microtubules. This compound consists of a six membered aromatic ring (A ring), a seven membered troponoid ring (C ring) and another seven membered aliphatic ring (B ring). Using molecular mechanics and molecular dynamics simulations as tools, conformational analysis of colchicine and its several important analogs were done. Molecular mechanics studies show that conformational space of these molecules have one low energy region. Taking the low energy minima as the starting conformation, molecular dynamics simulation for 100 pico seconds is done for each of the analogs and molecular dynamics simulation in solution is done for three representative compounds colchicine,isocolchicine and A-C compound. Internal coordinate trajectories show that the value of the dihedral angle C9-C7-C1-C14 (phi), (C7-C1 bond connects the A and C ring), is within 40 degrees to 50 degrees for all the compounds with fluctuations less than 15 degrees. These calculations indicate that there is an overall similarity in the dynamically averaged structure of all the drugs. The A ring and B ring of the compounds are more or less rigid. The C ring is somewhat flexible, the average conformation and motional properties show overall similarity. The potential energy curve and dynamics behaviour of colchicine and isocolchicine suggests that the difference in binding property of colchine and isocolchicine may originate from the positional difference of carbonyl oxygen and methoxy group of C ring, which is the only difference in the structures of the two compounds and this has no effect on the motional property and average conformations of these two compounds. From our study it is proposed that the movements occuring at various positions of the drug molecules are significantly correlated. It is suggested that such correlated motion may play an important role in the biological property of these compounds.

4-Chloro-7-nitrobenzofurazan↗

PubMed2005

A nonadditive methanol force field: bulk liquid and liquid-vapor interfacial properties via molecular dynamics simulations using a fluctuating charge model.

We study the bulk and interfacial properties of methanol via molecular dynamics simulations using a CHARMM (Chemistry at HARvard Molecular Mechanics) fluctuating charge force field. We discuss the parametrization of the electrostatic model as part of the ongoing CHARMM development for polarizable protein force fields. The bulk liquid properties are in agreement with available experimental data and competitive with existing fixed-charge and polarizable force fields. The liquid density and vaporization enthalpy are determined to be 0.809 g/cm3 and 8.9 kcal/mol compared to the experimental values of 0.787 g/cm3 and 8.94 kcal/mol, respectively. The liquid structure as indicated by radial distribution functions is in keeping with the most recent neutron diffraction results; the force field shows a slightly more ordered liquid, necessarily arising from the enhanced condensed phase electrostatics (as evidenced by an induced liquid phase dipole moment of 0.7 D), although the average coordination with two neighboring molecules is consistent with the experimental diffraction study as well as with recent density functional molecular dynamics calculations. The predicted surface tension of 19.66+/-1.03 dyn/cm is slightly lower than the experimental value of 22.6 dyn/cm, but still competitive with classical force fields. The interface demonstrates the preferential molecular orientation of molecules as observed via nonlinear optical spectroscopic methods. Finally, via canonical molecular dynamics simulations, we assess the model's ability to reproduce the vapor-liquid equilibrium from 298 to 423 K, the simulation data then used to obtain estimates of the model's critical temperature and density. The model predicts a critical temperature of 470.1 K and critical density of 0.312 g/cm3 compared to the experimental values of 512.65 K and 0.279 g/cm3, respectively. The model underestimates the critical temperature by 8% and overestimates the critical density by 10%, and in this sense is roughly equivalent to the underlying fixed-charge CHARMM22 force field.

Computer Simulation↗

PubMed2004

Photodissociation of diiodomethane in acetonitrile solution and fragment recombination into iso-diiodomethane studied with ab initio molecular dynamics simulations.

Photodissociation of diiodomethane (CH2I2) in acetonitrile solution has been studied with ab initio molecular dynamics simulations, which show how the iso-diiodomethane photoproduct (CH2I-I) can be formed. The first excited state, described by the "restricted open-shell Kohn-Sham" density functional method, is dissociative and photoexcitation of diiodomethane induces a breaking of one of the C-I bonds. In the simulations, we observe that energy dissipation to the surrounding solvent is essential in the formation of a stable iso-diiodomethane molecule. The caging effect of the solvent results in a recombination of the CH2I and I fragments into iso-diiodomethane on a picosecond time scale. The molecular dynamics simulations enable us to study the cage effect as well as the relaxation of intermediates and the distribution of energy. The CH2I fragment is formed vibrationally excited along the C-I stretching mode. After recombination of the CH2I and I fragments, iso-diiodomethane shows a strong vibration excitation in the CH2 group, which could be used as a fingerprint of the proposed mechanism.

Journal Article↗

PubMed1991

Molecular dynamics simulations of dinucleoside and dinucleoside-drug crystal hydrates.

Molecular dynamics simulations have been performed on the dinucleoside monophosphates rGpC and dCpG, the latter in its intercalation complex with the acridine drug proflavine. The simulations were performed on the crystal structures, with crystallographically-located solvent molecules. It was found that satisfactory results were best obtained with restraints placed on the movements of the water molecules. Motions of individual atoms have been examined in terms of rms fluctuations and anisotropy and correlation functions. Relative motions of groups (phosphates, sugars, bases and proflavine molecules) have been analysed.

Computer Simulation↗

PubMed2004

Insights into the phosphoryl-transfer mechanism of cAMP-dependent protein kinase from quantum chemical calculations and molecular dynamics simulations.

To investigate the molecular details of the phosphoryl-transfer mechanism catalyzed by cAMP-dependent protein kinase, we performed quantum mechanical (QM) calculations on a cluster model of the active site and molecular dynamics (MD) simulations of a ternary complex of the protein with Mg(2)ATP and a 20-residue peptide substrate. Overall, our theoretical results confirm the participation of the conserved aspartic acid, Asp(166), as an acid/base catalyst in the reaction mechanism catalyzed by protein kinases. The MD simulation shows that the contact between the nucleophilic serine side chain and the carboxylate group of Asp(166) is short and dynamically stable, whereas the QM study indicates that an Asp(166)-assisted pathway is structurally and energetically feasible and is in agreement with previous experimental results.

Catalytic Domain↗

PubMed1995

The effect of environment on the stability of an integral membrane helix: molecular dynamics simulations of surfactant protein C in chloroform, methanol and water.

A series of three molecular dynamics simulations at 300 K in explicit solvent environments of chloroform, methanol and water has been performed on the pulmonary surfactant lipoprotein, SP-C, comprising several consecutive valine residues in order to investigate the stability of the alpha-helical conformation. Two additional simulations were performed on truncated SP-C with a five-residue N-terminal deletion at 300 K and 500 K in water, the high temperature run in order to increase the rate of peptide denaturation. Indications of destabilization appear in chloroform during 1 ns while the SP-C alpha-helix is remarkably stable during 1 ns in methanol and water. In particular the polyvalyl part comprising residues Val15 to Val21 remains intact even at elevated temperature, and the valines do not disrupt the alpha-helical conformation. The valyl-rotamer sampling is partly restricted. Unfolding takes place successively along the primary sequence starting from the C-terminal end. Factors affecting polypeptide stability in molecular dynamics simulations are addressed. The intrinsic helix-forming tendency of valine residues and its dependence on the sequence context, and the role of the solvent environment in stabilizing or destabilizing an alpha-helical fold, are discussed.

Amino Acid Sequence↗

PubMed1996

Molecular dynamics simulations of synthetic peptide folding.

Because the time scale of protein folding is much greater than that of the widely used simulations of native structures, a detailed report of molecular dynamics simulations of folding has not been available. In this study, we included the average solvent effect in the potential functions to simplify the calculation of the solvent effect and carried out long molecular dynamics simulations of the alanine-based synthetic peptides at 274 K. From either an extended or a randomly generated conformation, the simulations approached a helix-coil equilibrium in about 3 ns. The multiple minima problem did not prevent helix folding. The calculated helical ratio of Ac-AAQ-AAAAQAAAAQAAY-NH2 was 47%, in good agreement with the circular dichroism measurement (about 50%). A helical segment with frayed ends was the most stable conformation, but the hydrophobic interaction favored the compact, distorted helix-turn-helix conformations. The transition between the two types of conformations occurred in a much larger time scale than helix propagation. The transient hydrogen bonds between the glutamine side chain and the backbone carbonyl group could reduce the free energy barrier of helix folding and unfolding. The substitution of a single alanine residue in the middle of the peptide with valine or glycine decreased the average helical ratio significantly, in agreement with experimental observations.

Alanine↗

PubMed2002

Molecular dynamics simulations revealed Ca(2+)-dependent conformational change of Calmodulin.

Molecular dynamics simulations were performed to simulate Ca(2+)-dependent conformational change of calmodulin (CaM). Simulations of the fully Ca(2+)-bound form of CaM (Holo-CaM) and the Ca(2+)-free form (Apo-CaM) were performed in solution for 4 ns starting from the X-ray crystal structure of Holo-CaM. A striking difference was observed between the trajectories of Holo-CaM and Apo-CaM: the central helix remained straight in the former but became largely bent in the latter. Also, the flexibility of Apo-CaM was higher than that of Holo-CaM. The results indicated that the bound Ca(2+) ions harden the structure of CaM.

Amino Acid Sequence↗

PubMed2003

The implementation of slab geometry for membrane-channel molecular dynamics simulations.

Slab geometric boundary conditions are applied in the molecular dynamics simulation of a simple membrane-channel system. The results of the simulation were compared to those of an analogous system using normal three-dimensional periodic boundary conditions. Analysis of the dynamics and electrostatics of the system show that slab geometric periodicity eliminates the artificial bulk water orientational polarization that is present while using normal three-dimensional periodicity. Furthermore, even though the water occupancy and volume of our simple channel is the same when using either method, the electrostatic properties are considerably different when using slab geometry. In particular, the orientational polarization of water is seen to be different in the interior of the channel. This gives rise to a markedly different electric field within the channel. We discuss the implications of slab geometry for the future simulation of this type of system and for the study of channel transport properties.

Alamethicin↗

PubMed2000

Molecular dynamics simulation of dipalmitoylphosphatidylcholine membrane with cholesterol sulfate.

Using the molecular dynamics simulation technique, we studied the changes occurring in a dipalmitoylphosphatidylcholine (DPPC):cholesterol (CH) membrane at 50 mol% sterol when cholesterol is replaced with cholesterol sulfate (CS). Our simulations were performed at constant pressure and temperature on a nanosecond time scale. We found that 1) the area per DPPC:CS heterodimer is greater than the area of the DPPC:CH heterodimer; 2) CS increases ordering of DPPC acyl chains, but to a lesser extent than CH; 3) the number of hydrogen bonds between DPPC and water is decreased in a CS-containing membrane, but CS forms more water hydrogen bonds than CH; and 4) the membrane dipole potential reverses its sign for a DPPC-CS membrane compared to a DPPC-CH bilayer. We also studied the changes occurring in lipid headgroup conformations and determined the location of CS molecules in the membrane. Our results are in good agreement with the data available from experiments.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed1996

Detailed description of an alpha helix-->pi bulge transition detected by molecular dynamics simulations of the p185c-erbB2 V659G transmembrane domain.

Molecular dynamics simulations of a 29-residue peptide including the transmembrane domain of the V659G mutant of the c-erbB2 protein demonstrate important dynamical behavior. Although the alpha helix is the structure commonly assumed for transmembrane hydrophobic segments, we found that hydrogen bond rearrangements can occur, giving rise to a structural deformation termed pi bulge stabilized by successive hydrogen bonds of pi helix type. A series of simulations enables us to give a detailed description, at the atomic level, of the alpha helix->pi bulge transition. The major consequence of this deformation covering one and a half turn of helix results in a noticeable shift around the helix axis of the C-Terminal residues relatively to those of the N-terminus. Such a deformation closely related to structural motifs described in the literature, induces a change in the distribution of the residues along the helix faces which could modulate the protein activity mediated by a dimerization process.

Amino Acid Sequence↗

PubMed1991

Molecular dynamics simulation of the aqueous solvation of sugars.

Recently, several molecular dynamics simulations of the aqueous solvation of carbohydrates have been reported. These studies represent the first theoretical picture available of the microscopic character of sugar solutions, and may provide explanations of the unusual and complex behavior of this class of molecules in solution. This paper will discuss two MD simulations of D-glucopyranose, including a free energy perturbation calculation of the anomeric free energy difference. Solvation was found to have little effect upon the mean conformational structure of the pyranoid rings, but the presence of solvent significantly affected the motions and orientations of the exocyclic groups. Adjacent functional groups of the sugar rings were found to mutually perturb one another's hydration, depending upon the local stereochemistry, which may prove to play a part in the observed anomeric preferences of the sugars. From a component analysis of the free energy of solvation of the two anomers of D-glucopyranose, it was found that a large solvation term favors the beta anomer, which is the form found to be preferred in aqueous solution.

Carbohydrates↗

PubMedDate not supplied

Molecular dynamics simulations and the conformational mobility of blood group oligosaccharides.

Molecular dynamics simulations were carried out without explicit consideration of solvent to explore the conformational mobility of blood group A and H oligosaccharides. The potential energy force field of Rasmussen and co-workers was used with the CHARMM program on a number of disaccharide and trisaccharide models composed of fucose, galactose, glucose, N-acetyl glucosamine, and N-acetyl galactosamine chosen to represent various fragments of blood group oligosaccharides. In agreement with results of earlier studies, stable chair conformations were found for each pyranoside from which no transitions were detected in simulations as long as 800 ps. Exocyclic dihedral angles, including that of C5-C6, generally show numerous transitions on a time scale of approximately 5-30 ps. The dihedral angles of some but not all glycosidic linkages of blood group oligosaccharides show transitions on the time scale of 30-50 ps, implying that the extent of internal motion in blood group oligosaccharides depends strongly on linkage stereochemistry. For certain blood group A and H oligosaccharides that show limited internal motion in these simulations, we argue that the calculations are consistent with our previous analysis of 1H nuclear Overhauser enhancement (NOE) data that imply single conformations over a wide range of temperature and solvent conditions. While the trajectories are consistent with 13C T1 values that have been interpreted as indicating rigid conformations, measurements of 13C-NOE and T1 as a function of magnetic field strength are proposed as an improved method for experimental detection of the internal motion that is suggested for certain oligosaccharides in these simulations. The results of these simulations differ substantially from those of peptides of a similar molecular weight in that the oligosaccharides show much less internal motion.

Blood Group Antigens↗