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PubMed2005

Molecular mechanics PBSA ligand binding energy and interaction of Efavirenz derivatives with HIV-1 reverse transcriptase.

In order to evaluate the properties of several HIV-1 reverse transcripase(RT) inhibitors, Efavirenz (SUSTIVA) and a set of its derivatives (benzoxazinones) have been placed into the nonnucleoside analogue binding site of the enzyme by molecular docking. The resulting geometries were used for a molecular dynamics simulation and binding energy calculations. The enzyme-inhibitor binding energies were estimated from experimental inhibitory activities (IC90). The correlation of the predicted and experimental binding energies were satisfactory acceptable as indicated by r2 = 0.865. Based on MD simulations, the obtained results indicate that the tight association of the ligand to the HIV-1 RT binding pocket was based on hydrogen bonding between Efavirenz's N1 and the oxygen of the backbone of Lys 101, with an estimated average distance of 1.88 A. Moreover, electrostatic interaction was mainly contributed by two amino acid residues in the binding site; Lys 101 and His 235. MD simulations open the possibility to study the reaction of the flexible enzyme to those substances as well as the overall affinity.

Adipates↗

PubMed1993

Solution structure of lariat RNA by 500 MHz NMR spectroscopy and molecular dynamics studies in water.

A 500 MHz NMR study of the lariat RNA tetramer 1 and pentamer 2 mimicking the naturally occurring lariat RNA is reported. The conformational properties of 1 and 2 were compared with those of a linear branched RNA tetramer 3, which show that the conformational features of the two lariat RNAs, 1 and 2, are quite constrained and significantly different from those observed for the linear branched RNA tetramer 3. The conformation of all sugar residues forming the lariat ring in 1 and 2 are locked in a rigid South-type conformation. All residues in both lariat RNAs have a high population of gamma+ (67-85%) and beta t (95-100%) rotamers except guanosine where the gamma+ population is low. The conformation around the glycosidic bond is anti for all residues except for guanosine where NOE data indicates an equilibrium of syn<-->anti. In both lariat RNAs, 1 and 2, the temperature dependent 1H and 31P chemical shifts as well as the oligomerization shifts, with respect to adenosine 2',3',5'-triethyl-phosphate (Sund et al., 1992, Tetrahedron 48, 695) suggests that the 3'-->5' linked U4 or C4 residue is stacked on guanosine. Subsequently, 1H-1H, 1H-31P and 13C-31P coupling constants derived torsional constraints were used for molecular dynamics study in water with counter sodium ions for a total of 226 ps. The MD simulations were first carried out with harmonic torsional constraints which were derived from J couplings (0-86 ps) and then completely without constraints (96-226 ps). The lack of any major changes in the conformation of the two lariat-RNA structures upon releasing the NMR constraints indicate that the conformers generated in the MD simulation in water agree well with the structural features suggested by experimental observables. This means that the ensemble of conformers generated during the MD trajectory of 226 ps are not artificially held in these conformations due to the NMR constraints, suggesting that these conformers can be considered to be good representatives of the actual NMR observed solution structures.

Base Sequence↗

PubMed2003

Macrocycle conformation and self-inclusion phenomena in octakis(3-O-butanoyl-2,6-di-O-pentyl)-gamma-cyclodextrin (Lipodex E) by NMR spectroscopy and molecular dynamics.

Octakis(3-O-butanoyl-2,6-di-O-pentyl)-gamma-cyclodextrin (Lipodex E) is a lipophilic chiral selector successfully used for the enantioselective gas chromatographic separation of a multitude of racemic analytes. NMR data (13C chemical shifts, 3J(HH), rotating frame NOEs (ROEs)) and molecular dynamics (MD) simulations point out that the macrocycle is distorted with respect to the canonical truncated-cone shape of native cyclodextrins, although C(8) symmetry is retained on the NMR timescale. ROE data and MD trajectories provide evidence for self-inclusion of one 6-O-pentyl pendant chain within the cavity of Lipodex E. The interpretation of long-range and low-intensity ROEs is supported by the calculation of average internuclear distances by using the radial distribution function (RDF) calculated from MD trajectories. MD simulations are eventually used to compare the flexibility of the macrocycle of Lipodex E with that of native gammaCD.

Computer Simulation↗

PubMed2006

Kinetics of triscarbonato uranyl reduction by aqueous ferrous iron: a theoretical study.

Uranium is a pollutant whose mobility is strongly dependent on its oxidation state. While U(VI) in the form of the uranyl cation is readily reduced by a range of natural reductants, by contrast complexation of uranyl by carbonate greatly reduces its reduction potential and imposes increased electron transfer (ET) distances. Very little is known about the elementary processes involved in uranium reduction from U(VI) to U(V) to U(IV) in general. In this study, we examine the theoretical kinetics of ET from ferrous iron to triscarbonato uranyl in aqueous solution. A combination of molecular dynamics (MD) simulations and density functional theory (DFT) electronic structure calculations is employed to compute the parameters that enter into Marcus' ET model, including the thermodynamic driving forces, reorganization energies, and electronic coupling matrix elements. MD simulations predict that two ferrous iron atoms will bind in an inner-sphere fashion to the three-membered carbonate ring of triscarbonato uranyl, forming the charge-neutral ternary Fe(2)UO(2)(CO(3))(3)(H(2)O)(8) complex. Through a sequential proton-coupled electron-transfer mechanism (PCET), the first ET step converting U(VI) to U(V) is predicted by DFT to occur with an electronic barrier that corresponds to a rate on the order of approximately 1 s(-1). The second ET step converting U(V) to U(IV) is predicted to be significantly endergonic. Therefore, U(V) is a stabilized end product in this ET system, in agreement with experiment.

Journal Article↗

PubMed2001

Molecular dynamics studies of sequence-directed curvature in bending locus of trypanosome kinetoplast DNA.

The macroscopic curvature induced in the double helical B-DNA by regularly repeated adenine tracts (A-tracts) plays an exceptional role in structural studies of DNA because this effect presents the most well documented example of sequence specific conformational modulations. Recently, a new hypothesis of its physical origin has been put forward. According to it, the intrinsic bends in B-DNA may represent one of the consequences of the compressed frustrated state of its backbone. The compressed backbone hypothesis agrees with many data and explains some controversial experimental observations. The original arguments of this theory came out from MD simulations of a DNA fragment with a strong bending propensity. Its sequence, however, was not experimental. It was constructed empirically so as to maximize the magnitude of bending in calculations. To make sure that our computations reproduce the experimental effect we carried out similar simulations with an A-tract repeat of a natural base pair sequence found in a bent locus of a minicircle DNA. We demonstrate spontaneous development of static curvature in the course of MD simulations excluding any initial bias except the base pair sequence. Its direction and magnitude agree with experimental estimates. The results confirm earlier qualitative conclusions and agree with the hypothesis of a compressed backbone as the origin of static bending in B-DNA.

Animals↗

PubMed2000

A "structural" water molecule in the family of fatty acid binding proteins.

A single water molecule (w135), buried within the structure of rat intestinal fatty acid binding protein (I-FABP), is investigated by NMR, molecular dynamics simulations, and analysis of known crystal structures. An ordered water molecule was found in structurally analogous position in 24 crystal structures of nine different members of the family of fatty acid binding proteins. There is a remarkable conservation of the local structure near the w135 binding site among different proteins from this family. NMR cross-relaxation measurements imply that w135 is present in the I-FABP:ANS (1-sulfonato-8-(1')anilinonaphthalene) complex in solution with the residence time of >300 ps. Mean-square positional fluctuations of w135 oxygen observed in MD simulations (0.18 and 0.13 A2) are comparable in magnitude to fluctuations exhibited by the backbone atoms and result from highly constrained binding pocket as revealed by Voronoi volumes (averages of 27.0 +/- 1.8 A3 and 24.7 +/- 2.2 A3 for the two simulations). Escape of w135 from its binding pocket was observed only in one MD simulation. The escape process was initiated by interactions with external water molecules and was accompanied by large deformations in beta-strands D and E. Immediately before the release, w135 assumed three distinct states that differ in hydrogen bonding topology and persisted for about 15 ps each. Computer simulations suggest that escape of w135 from the I-FABP matrix is primarily determined by conformational fluctuations of the protein backbone and interactions with external water molecules.

Animals↗

PubMed2004

Two-dimensional Yukawa liquids: correlation and dynamics.

A combined theoretical and molecular dynamics (MD) simulation study of the collective modes and their dispersion in a two-dimensional Yukawa system in the strongly coupled liquid state is presented. The theoretical analysis relies upon the quasilocalized charge approximation; the MD simulation generates static pair correlation functions and dynamical current-current correlation spectra.

Journal Article↗

PubMed1997

Channels formed by the transmembrane helix of phospholamban: a simulation study.

Phospholamban is a small membrane protein which can form cation selective ion channels in lipid bilayers. Each subunit contains a single, largely hydrophobic transmembrane helix. The helices are thought to assemble as a pentameric and approximately parallel bundle surrounding a central pore. A model of this assembly (PDB code IPSL) has been used as the starting point for molecular dynamics (MD) simulations of a system consisting of the pentameric helix bundle, plus 217 water molecules located within and at either mouth of the pore. Interhelix distance restraints were employed to maintain the integrity of the helix bundle during a 500 ps MD simulation. Water molecules within the pore exhibited reduced diffusional and rotational mobility. Interactions between the alpha-helix dipoles and the water dipoles, the latter aligned anti-parallel to the former, contribute to the stability of the system. Analysis of the potential energy of interaction of a K+ ion as it was moved through the pore suggested that unfavourable interactions of the cation with the aligned helix dipoles at the N-terminal mouth were overcome by favourable ion-water interactions. Comparable analysis for a Cl ion revealed that the ion-(pore + water) interactions were unfavourable along the whole of the pore, increasingly so from the N- to the C-terminal mouth. Overall, the interaction energy profiles were consistent with a pore selective for cations over anions. Pore radius profiles were used to predict a channel conductance of 50 to 70 ps in 0.2 M KCl, which compares well with an experimental value of 100 ps.

Calcium-Binding Proteins↗

PubMed2005

Regiospecificity of human cytochrome P450 1A1-mediated oxidations: the role of steric effects.

Cytochrome P450 1A1 oxidizes a diverse range of substrates, including the procarcinogenic xenobiotic benzo[a]pyrene (B[a]P) and endogenous fatty acid precursors of prostaglandins, such as arachidonic acid (AA) and eicosapentaenoic acid (EA). We have investigated the extent to which enzyme-substrate interactions govern regio- and stereoselectivity of oxidation of these compounds by using docking and molecular dynamics (MD) simulations to examine the likelihood of substrate oxidation at various sites. Due to structural differences between the substrates analyzed, B[a]P and its diols (planar, rigid), and the fatty acids AA and EA (long, flexible), different docking strategies were required. B[a]P, B[a]P-7,8-diols, (+) 7S,8S- and (-) 7R,8R-diols, were docked into the active site of a homology model of P450 1A1 using an automated routine, Affinity (Accelrys, San Diego, CA). AA and EA, on the other hand, required a series of restrained MD simulations to obtain a variety of productive binding modes. All complexes were evaluated by MD-based in silico site scoring to predict product profiles based on certain geometric criteria, such as angle and distance of a given substrate atom from the ferryl oxygen. For all substrates studied, the in vitro profiles were generally reflected by the in silico scores, which suggests that steric factors play a key role in determining regiospecificity in P450 1A1-mediated oxidations. We have also shown that molecular dynamics simulations may be very useful in determination of product profiles for structurally diverse substrates of P450 enzymes.

Binding Sites↗

PubMed2006

Distance between a native cofactor and a spin label in the reaction centre of Rhodobacter sphaeroides by a two-frequency pulsed electron paramagnetic resonance method and molecular dynamics simulations.

The distance between the paramagnetic state of a native cofactor and a spin label is measured in the photosynthetic reaction centre from the bacterium Rhodobacter sphaeroides R26. A two-frequency pulsed electron paramagnetic resonance method [double-electron-electron spin resonance (DEER)] is used. A distance of 3.05 nm between the semiquinone anion state of the primary acceptor (Q(A)) and the spin label at the native cysteine at position 156 in the H-subunit is found. Molecular-dynamics (MD) simulations are performed to interpret the distance. A 6 ns run comprising the entire RC protein yields a distance distribution that is close to the experimental one. The average distance found by the MD simulation is smaller than the distance obtained by DEER by at least 0.2 nm. To better represent the experiments performed at low temperature (60K), a MD method to mimic the freezing-in of the room-temperature conformations is introduced. Both MD methods yield similar distances, but the second method has a trend towards a wider distance distribution.

Anions↗

PubMed2005

Simulations on the thermal decomposition of a poly(dimethylsiloxane) polymer using the ReaxFF reactive force field.

To investigate the failure of the poly(dimethylsiloxane) polymer (PDMS) at high temperatures and pressures and in the presence of various additives, we have expanded the ReaxFF reactive force field to describe carbon-silicon systems. From molecular dynamics (MD) simulations using ReaxFF we find initial thermal decomposition products of PDMS to be CH(3) radical and the associated polymer radical, indicating that decomposition and subsequent cross-linking of the polymer is initiated by Si-C bond cleavage, in agreement with experimental observations. Secondary reactions involving these CH(3) radicals lead primarily to formation of methane. We studied temperature and pressure dependence of PDMS decomposition by following the rate of production of methane in the ReaxFF MD simulations. We tracked the temperature dependency of the methane production to extract Arrhenius parameters for the failure modes of PDMS. Furthermore, we found that at increased pressures the rate of PDMS decomposition drops considerably, leading to the formation of fewer CH(3) radicals and methane molecules. Finally, we studied the influence of various additives on PDMS stability. We found that the addition of water or a SiO(2) slab has no direct effect on the short-term stability of PDMS, but addition of reactive species such as ozone leads to significantly lower PDMS decomposition temperature. The addition of nitrogen monoxide does not significantly alter the degradation temperature but does retard the initial production of methane and C(2) hydrocarbons until the nitrogen monoxide is depleted. These results, and their good agreement with available experimental data, demonstrate that ReaxFF provides a useful computational tool for studying the chemical stability of polymers.

Journal Article↗

PubMed2000

The prion protein globular domain and disease-related mutants studied by molecular dynamics simulations.

In humans, familial forms of transmissible spongiform encephalopathies (TSE; "prion diseases") have been shown to segregate with the exchange of individual amino acids in the prion protein (PrP) sequence. We used the NMR structure of the globular domain of mouse PrP in the cellular form (PrP(C)) as a starting point for investigations by long-time molecular dynamics (MD) simulations at ambient temperature of likely impacts of such mutations on the PrP(C) structure, making use of the fact that species-related amino acid replacements between mouse PrP and human PrP are spatially well separated from the disease-related mutations in human PrP. In the MD simulations these amino acid substitutions were found to have a variety of different effects on the protein structure, with some species showing altered packing of regular secondary structure elements, while other mutants showed no or only strictly localized changes of the structure near the variant amino acid. The fact that some of the disease-related amino acid exchanges cause no measurable change of the PrP(C) structure indicates that their influence on the conformational transition to the scrapie form of PrP may be due to modified intermolecular interactions during the aggregation process.

Amino Acid Substitution↗

PubMed2005

Asymmetry of lipid bilayers induced by monovalent salt: atomistic molecular-dynamics study.

Interactions between salt ions and lipid components of biological membranes are essential for the structure, stability, and functions of the membranes. The specific ionic composition of aqueous buffers inside and outside of the cell is known to differ considerably. To model such a situation we perform atomistic molecular-dynamics (MD) simulations of a single-component phosphatidylcholine lipid bilayer which separates two aqueous reservoirs with and without NaCl salt. To implement the difference in electrolyte composition near two membrane sides, a double bilayer setup (i.e., two bilayers in a simulation box) is employed. It turns out that monovalent salt, being in contact with one leaflet only, induces a pronounced asymmetry in the structural, electrostatic, and dynamical properties of bilayer leaflets after 50 ns of MD simulations. Binding of sodium ions to the carbonyl region of the leaflet which is in contact with salt results in the formation of "Na-lipids" complexes and, correspondingly, reduces mobility of lipids of this leaflet. In turn, attractive interactions of chloride ions (mainly located in the aqueous phase close to the water-lipid interface) with choline lipid groups lead to a substantial (more vertical) reorientation of postphatidylcholine headgroups of the leaflet adjoined to salt. The difference in headgroup orientation on two sides of a bilayer, being coupled with salt-induced reorientation of water dipoles, leads to a notable asymmetry in the charge-density profiles and electrostatic potentials of bilayer constitutes of the two leaflets. Although the overall charge density of the bilayer is found to be almost insensitive to the presence of salt, a slight asymmetry in the charge distribution between the two bilayer leaflets results in a nonzero potential difference of about 85 mV between the two water phases. Thus, a transmembrane potential of the order of the membrane potential in a cell can arise without ionic charge imbalance between two aqueous compartments.

Journal Article↗

PubMed1999

Computational studies on mutant protein stability: The correlation between surface thermal expansion and protein stability.

Thermal stability of mutant proteins has been investigated using temperature dependent molecular dynamics (MD) simulations in vacuo. The numerical modeling was aimed at mimicking protein expansion upon heating. After the conditions for an expanding protein accessible surface area were established for T4 lysozyme and barnase wild-type proteins, MD simulations were carried out under the same conditions using the crystal structures of several mutant proteins. The computed thermal expansion of the accessible surface area of mutant proteins was found to be strongly correlated with their experimentally measured stabilities. A similar, albeit weaker, correlation was observed for model mutant proteins. This opens the possibility of obtaining stability information directly from protein structure.

Bacterial Proteins↗

PubMed2003

Implicit solvent model estimates of the stability of model structures of the alamethicin channel.

Alamethicin is a hydrophobic helical peptide of 20 residues, which oligomerizes to form ion-conducting channels in membranes. The behavior of an intact alamethicin channel in POPC bilayers was recently studied, using 2 ns molecular dynamics (MD) simulations of a model hexameric channel. These simulations produced numerous conformations of the channel. In the present study, we used 11 of these channel conformations and carried out continuum-solvent model calculations, similar to those used for the monomers in our previous studies, to investigate the energetics of the channel inside the lipid bilayer. Our results suggest that, out of the 11 channel conformations produced by the MD simulations, only four are stable inside the lipid bilayer, with water-to-membrane free energies of transfer ranging from approximately -6 to approximately -10 kcal/mol. Analysis of the results suggests two causes for the apparent instability of the remainder of the structures inside the lipid bilayer, both resulting from the desolvation of channel polar groups (i.e. their transfer from the aqueous phase into the bilayer). The first is specific, uncompensated backbone hydrogen bonds, which exist in the region of the channel exposed to the hydrocarbon of the lipid bilayer. The second is exposure of intra-pore water molecules to the surrounding lipid. Thus, the association of these structures with the membrane involves a large electrostatic desolvation free-energy penalty. The apparent conflict between continuum-solvent and MD calculations, and its significance for the interpretation of membrane proteins simulations, are discussed.

Alamethicin↗

PubMed2005

Molecular modeling and molecular dynamics simulation of the human A2B adenosine receptor. The study of the possible binding modes of the A2B receptor antagonists.

A molecular model of the human A(2B) adenosine receptor containing seven transmembrane alpha helices connected by three intracellular and three extracellular hydrophilic loops had been constructed. A molecular docking of seven structurally diverse xanthine antagonists of the A(2B) receptor was performed, and the differences in their binding modes were investigated. The 1 ns molecular dynamics (MD) simulations of several obtained ligand-receptor complexes inserted into the phospholipid bilayer were carried out. The conformational changes of the A(2B) receptor occurring during MD simulations were explored, and the stable binding modes of the studied antagonists were determined. According to the models presented in this work, the involvement of the His251, Asn282, Ser92, Thr89, and some aromatic residues in ligand recognition was determined. The obtained binding modes of the A(2B) antagonists demonstrate good agreement with the site-directed mutagenesis data.

Adenosine A2 Receptor Antagonists↗

PubMed2006

Molecular dynamics simulations of arachidonic acid complexes with COX-1 and COX-2: insights into equilibrium behavior.

The cyclooxygenase (COX) enzymes are responsible for the committed step in prostaglandin biosynthesis, the generation of prostaglandin H(2). As a result, these enzymes are pharmacologically important targets for nonsteroidal antiinflammatory drugs, such as aspirin and newer COX-2 selective inhibitors. The cyclooxygenases are functional homodimers, and each subunit contains both a cyclooxygenase and a peroxidase active site. These enzymes are quite interesting mechanistically, as the conversion of arachidonic acid to prostaglandin H(2) requires two oxygenation and two cyclization reactions, resulting in the formation of five new chiral centers with nearly absolute regio- and stereochemical fidelity. We have used molecular dynamics (MD) simulations to investigate the equilibrium behavior of both COX-1 and COX-2 enzyme isoforms with bound arachidonate. These simulations were compared with reference simulations of arachidonate in solution to explore the effect of enzyme on substrate conformation and positioning in the active site. The simulations suggest that the substrate has greater conformational freedom in the COX-2 active site, consistent with the larger COX-2 active site volume observed in X-ray crystal structures. The simulations reveal different conformational behavior for arachidonate in each subunit over the course of extended equilibrium MD simulations. The simulations also provide detailed information for several protein channels that might be important for oxygen and water transport to or from active sites or for intermediate trafficking between the cyclooxygenase and peroxidase active sites. The detailed comparisons for COX-1 versus COX-2 active site structural fluctuations may also provide useful information for design of new isozyme-selective inhibitors.

Arachidonic Acid↗

PubMed1991

Characterization of proline-containing right-handed alpha-helix by molecular dynamics studies.

Proline residues play a special role in shaping the secondary and tertiary structures of proteins. Many of these aspects have been studied in great detail. Current interest lies in elucidating the structure of right-handed alpha-helical fragments which contain proline in the middle of the helix. Such structures play an important role in membrane proteins and in the tight packing of globular proteins. Analysis of several crystal structures and energy minimization using flexible geometry have elucidated the nature of the bend produced by proline in the right-handed alpha-helical structure. Molecular dynamics (MD) simulation studies are ideally suited to characterize rigidity or flexibility in different parts of the molecule and can also give an idea of various conformations of the molecule which can exist at a given temperature. Hence, MD studies on Ace-(Ala)6-Pro-(Ala)3-NHMe have been carried out for 100 ps after equilibration and the resulting trajectories have been analyzed. Information regarding the average values, r.m.s. fluctuations of internal parameters and the time spent in different conformations are discussed. Energy minimization has been carried out on selected MD simulated points in order to analyze the characteristics of different conformations.

Journal Article↗