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At least 829 records · Page 46Linked to original sources
PubMed1998

Conformational sampling of CDR-H3 in antibodies by multicanonical molecular dynamics simulation.

The diversity in the lengths and the amino acid sequences of the third complementarity determining region of the antibody heavy chain (CDR-H3) has made it difficult to establish a relationship between the sequences and the tertiary structures, in contrast to the other CDRs, which are classified by their canonical structures. Enhanced conformational sampling of two different CDR-H3s was performed by multicanonical molecular dynamics (multicanonical MD) simulation while restricting the base structures, with and without the other surrounding CDR segments. The results showed that the multicanonical MD sampled a much larger conformational space than the conventional MD, independent of the initial conformations of the simulations. When the other CDRs surrounding the CDR-H3 segments were included in the calculations, the predominant conformations at 300 K corresponded to the X-ray crystal structures. When only the single CDR-H3 loops were considered with the restricted base structures, a greater number of different conformations were sampled as putative loops, but only a small number of stable conformations appeared at 300 K. Analyses of the resultant conformations revealed a structural role for the glycine, when it is located at position three residues before the last residue of CDR-H3 (Gly-X-X-last residue), coincident with the statistical tendencies of many antibody crystal structures. This reflects the general consistency between the energetically stable conformations and the empirically observed conformations. The current method is expected to be applicable to the structural modeling and the design of antibodies, especially for the inherently flexible loops.

Algorithms↗
PubMed2004

Dynamics of simple liquids at heterogeneous surfaces: molecular-dynamics simulations and hydrodynamic description.

In this paper we consider the effect of surface heterogeneity on the slippage of fluid, using two complementary approaches. First, MD simulations of a corrugated hydrophobic surface have been performed. A dewetting transition, leading to a super-hydrophobic state, is observed for pressure below a "capillary" pressure. Conversely, a very large slippage of the fluid on this composite interface is found in this super-hydrophobic state. Second, we propose a macroscopic estimate of the effective slip length on the basis of continuum hydrodynamics, in order to rationalize the previous MD results. This calculation allows to estimate the effect of a heterogeneous slip length pattern at the composite interface. Comparison between the two approaches shows that they are in good agreement at low pressure, but highlights the role of the exact shape of the liquid-vapor interface at higher pressure. These results confirm that small variations in the roughness of a surface can lead to huge differences in the slip effect. On the basis of these results, we propose some guidelines to design highly slippery surfaces, motivated by potential applications in microfluidics.

Journal Article↗
PubMed2006

Three-dimensional model of the human aromatase enzyme and density functional parameterization of the iron-containing protoporphyrin IX for a molecular dynamics study of heme-cysteinato cytochromes.

Mammalian cytochromes P450 (CYP) are enzymes of great biological and pharmaco-toxicological relevance. Due to their membrane-bound nature, the structural characterization of these proteins is extremely difficult, and therefore computational techniques, such as comparative modeling, may help obtaining reliable structures of members of this family. An important feature of CYP is the presence of an iron-containing porphyrin group at the enzyme active site. This calls for quantum chemical calculations to derive charges and parameters suitable for classical force field-based investigations of this proteins family. In this report, we first carried out density functional theory (DFT) computations to derive suitable charges for the Fe2+-containing heme group of P450 enzymes. Then, by means of the homology modeling technique, and taking advantage of the recently published crystal structure of the human CYP2C9, we built a new model of the human aromatase (CYP19) enzyme. Furthermore, to study the thermal stability of the new model as well as to test the suitability of the new DFT-based heme parameters, molecular dynamics (MD) simulations were carried out on both CYP2C9 and CYP19. Finally, the last few ns of aromatase MD trajectories were investigated following the essential dynamics protocol that allowed the detection of some correlated motions among some protein domains.

Animals↗
PubMed1987

Aspects of model building applied to the C-terminal domain of the L12 protein from chloroplast ribosomes: a molecular dynamics study.

A 170 picosecond molecular dynamics trajectory has been calculated starting from a model-built structure of chloroplast CTF. Local conformational changes occur during the equilibration period. Thereafter, a dynamically stable structure is attained. The conformational changes involve a turn connecting two structural subdomains which has an amino acid insertion and several substitutions with respect to the E. coli sequence. Potential energy minimisation alone fails to detect such a change. The overall folding and atomic positional fluctuations are very similar to those found in MD simulations of the E. coli molecule. The combined use of computer graphics based model building and MD calculations has lead to a thermally stable putative structure for the chloroplast CTF.

Chemical Phenomena↗
PubMed2004

Cu(II) in liquid ammonia: an approach by hybrid quantum-mechanical/molecular-mechanical molecular dynamics simulation.

To investigate the solvation structure of the Cu(II) ion in liquid ammonia, ab initio quantum-mechanical/molecular-mechanical (QM/MM) molecular dynamics (MD) simulations were carried out at Hartree Fock (HF) and hybrid density functional theory (B3 LYP) levels. A sixfold-coordinated species was found to be predominant in the HF case whereas five- and sixfold-coordinated complexes were obtained in a ratio 2:1 from the B3 LYP simulation. In contrast to hydrated Cu(II), which exhibits a typical Jahn-Teller distortion, the geometrical arrangement of ligand molecules in the case of ammonia can be described as a [2 + 4] ([2 + 3]) configuration with 4 (3) elongated copper-nitrogen bonds. First shell solvent exchange reactions at picosecond rate took place in both HF and B3 LYP simulations, again in contrast to the more stable sixfold-coordinated hydrate. NH3 ligands apparently lead to strongly accelerated dynamics of the Cu(II) solvate due to the "inverse" [2 + 4] structure with its larger number of elongated copper-ligand bonds. Several dynamical properties, such as mean ligand residence times or ion-ligand stretching frequencies, prove the high lability of the solvated complex.

Journal Article↗
PubMed2005

Molecular dynamics simulation of a high-affinity antibody-protein complex: the binding site is a mosaic of locally flexible and preorganized rigid regions.

One nanosecond molecular dynamic (MD) simulation of anti-hen egg white lysozyme (HEL) antibody HyHEL63 (HH63) complexed with HEL reveals rigid and flexible regions of the HH63 binding site. Fifty conformations, extracted from the MD trajectory at regular time intervals were superimposed on HH63-HEL X-ray crystal structure, and the root mean squared deviations (RMSDs) and deviations in Calpha atom positions between the X-ray structure and the MD conformer were measured. Residue positions showing the large deviations in both light chain and heavy chain of the antibody were same in all the MD conformers. The residue positions showing smallest deviations were same for all the conformers in the case of light chain, whereas relatively variable in the heavy chain. Positions of large and small deviations fell in the complementarity determining regions (CDRs), for both heavy and light chains. The larger deviations were in CDR-2 of light and CDR-1 of heavy chain. Smaller deviations were in CDR-3 of light and CDR-2 and CDR-3 of heavy chains. The large and small deviating regions highlight flexible and rigid regions of HH63 binding site and suggest a mosaic binding mechanism, including both "induced fit" and preconfigured "lock-and-key" type of binding. Combined "induced fit" and "lock-and-key" binding would be a better definition for the formation of large complexes, which bury larger surface area on binding, as in the case of antibody-HEL complex. We further show that flexible regions, comprising mostly charged and polar residues, form intermolecular interactions with HEL, whereas rigid regions do not. Electrostatic complementarity between HH63 and HEL also imply optimized binding affinity. Flexible and rigid regions of a high-affinity antibody are selected during the affinity maturation of the antibody and have specific functional significance. The functional importance of local inherently flexible regions is to establish intermolecular contacts or they play a key role in molecular recognition, whereas local rigid regions provide the structural framework.

Antibodies↗
PubMed1996

Spin-labeled nucleotide mobility in the boundary of the EcoRI endonuclease binding site.

A complex consisting of the EcoRI endonuclease site-specifically bound to spin-labeled DNA 26mers was prepared to provide a model system for studying possible conformational changes resulting from protein binding. EPR was used to monitor the mobility of the spin labels that were strategically placed in position 6, 9, or 11 with respect to the dyad axis of the 26mer. These positions are located within the flanking region on either side of the EcoRI hexamer binding site. This allows the monitoring of potential distal structural changes in the DNA helix caused by protein binding. The spectral line shapes indicate that the spin label closest to the EcoRI endonuclease binding site, i.e., in position 6, is most influenced by the binding event. The EPR data are analyzed according to a model that distinguishes between spectral effects due to a change in the hydrodynamic shape of the complex and those resulting from local variations in the spin-label mobility as characterized by a local order parameter S. S reflecting the motional restriction of the spin-labeled base is 0.20 +/- 0.01 for all three oligomers as well as for the two complexes with the label in position 9 or 11, while the position 6 labeled complex yields S = 0.25. To further evaluate the origin of the slightly larger EPR effect observed with position 6 labeled material, molecular dynamics (MD) simulations were used to explore the space accessible to the probes in positions 6, 9, and 11. MD results gave similar nitroxide trajectories for all three labeled 26mers in the absence or presence of EcoRI. Thus, the small position 6 effect is attributed to a structural distortion in the major groove of the DNA at this location possibly corresponding to a bend induced by protein binding. The observation that the spectral changes are small indicates the absence of any significant structural disruption being propagated along the helix as a result of protein binding. Also, the fact that the line shape of the 26mers did not change as expected from hydrodynamic theory in view of the significant increase in molecular volume upon protein binding suggests that there are additional relaxation processes involving the protein and nucleic acid.

Binding Sites↗
PubMed1997

Solution structure of synthetic peptide inhibitor and substrate of cAMP-dependent protein kinase. A study by 2D H NMR and molecular dynamics.

Peptides derived from the inhibitor of cAMP-dependent protein kinase. PKI, have been studied by 2D 1H NMR techniques. These include the inhibitor PKI(6-22), the substrate [Ala20-Ser21]PKI(5-24), and a phosphorylated form of the latter [Ala20-Ser21P]PKI(5-24). A homologous fold was found in the three peptides which consisted of an N-terminal segment in helical conformation to residue 13 and a C-terminal segment poorly defined conformationally. A parallel study was carried out by molecular dynamics (MD) for the inhibitor peptide PKI(5-24). The N-terminal helix, as observed in the crystal structure of the catalytic subunit-PKI(5-24) complex, was conserved in the MD simulations with the enzyme-free inhibitor. Similarly the Gly14-Gly17 turn was apparent in all MD structures, whereas the C-terminal region, residues 18-24, was directed towards the N-terminal helix in contrast to the extended conformation of this segment pointing away from the N-terminal helix in the crystal structure. This is primarily due to ionic interaction between Asp9 and Arg15. Indeed, a detailed analysis of the NOE contacts by NOESY at low temperature (2 degrees C) shows the occurrence of pH-dependent contacts with Phe10. We conclude that the binding of short inhibitors, such as PKI(5-24), to the enzyme involves a conformational rearrangement of the C-terminal region. The substrate [Ala20-Ser21]PKI(5-24) and the product [Ala20-Ser21P]PKI(5-24), give very similar structures with local rearrangements involving some of the side chains.

Amino Acid Sequence↗
PubMed1999

Combined Monte Carlo and molecular dynamics simulation of fully hydrated dioleyl and palmitoyl-oleyl phosphatidylcholine lipid bilayers.

We have applied a new equilibration procedure for the atomic level simulation of a hydrated lipid bilayer to hydrated bilayers of dioleyl-phosphatidylcholine (DOPC) and palmitoyl-oleyl phosphatidylcholine (POPC). The procedure consists of alternating molecular dynamics trajectory calculations in a constant surface tension and temperature ensemble with configurational bias Monte Carlo moves to different regions of the configuration space of the bilayer in a constant volume and temperature ensemble. The procedure is applied to bilayers of 128 molecules of POPC with 4628 water molecules, and 128 molecules of DOPC with 4825 water molecules. Progress toward equilibration is almost three times as fast in central processing unit (CPU) time compared with a purely molecular dynamics (MD) simulation. Equilibration is complete, as judged by the lack of energy drift in 200-ps runs of continuous MD. After the equilibrium state was reached, as determined by agreement between the simulation volume per lipid molecule with experiment, continuous MD was run in an ensemble in which the lateral area was restrained to fluctuate about a mean value and a pressure of 1 atm applied normal to the bilayer surface. Three separate continuous MD runs, 200 ps in duration each, separated by 10,000 CBMC steps, were carried out for each system. Properties of the systems were calculated and averaged over the three separate runs. Results of the simulations are presented and compared with experimental data and with other recent simulations of POPC and DOPC. Analysis of the hydration environment in the headgroups supports a mechanism by which unsaturation contributes to reduced transition temperatures. In this view, the relatively horizontal orientation of the unsaturated bond increases the area per lipid, resulting in increased water penetration between the headgroups. As a result the headgroup-headgroup interactions are attenuated and shielded, and this contributes to the lowered transition temperature.

Lipid Bilayers↗
PubMed2004

Ribosomal RNA kink-turn motif--a flexible molecular hinge.

Ribosomal RNA K-turn motifs are asymmetric internal loops characterized by a sharp bend in the phosphodiester backbone resulting in "V" shaped structures, recurrently observed in ribosomes and showing a high degree of sequence conservation. We have carried out extended explicit solvent molecular dynamics simulations of selected K-turns, in order to investigate their intrinsic structural and dynamical properties. The simulations reveal an unprecedented dynamical flexibility of the K-turns around their X-ray geometries. The K-turns sample, on the nanosecond timescale, different conformational substates. The overall behavior of the simulations suggests that the sampled geometries are essentially isoenergetic and separated by minimal energy barriers. The nanosecond dynamics of isolated K-turns can be qualitatively considered as motion of two rigid helix stems controlled by a very flexible internal loop which then leads to substantial hinge-like motions between the two stems. This internal dynamics of K-turns is strikingly different for example from the bacterial 5S rRNA Loop E motif or BWYV frameshifting pseudoknot which appear to be rigid in the same type of simulations. Bistability and flexibility of K-turns was also suggested by several recent biochemical studies. Although the results of MD simulations should be considered as a qualitative picture of the K-turn dynamics due to force field and sampling limitations, the main advantage of the MD technique is its ability to investigate the region close to K-turn ribosomal-like geometries. This part of the conformational space is not well characterized by the solution experiments due to large-scale conformational changes seen in the experiments. We suggest that K-turns are well suited to act as flexible structural elements of ribosomal RNA. They can for example be involved in mediation of large-scale motions or they can allow a smooth assembling of the other parts of the ribosome.

Base Sequence↗
PubMed2007

Coarse-grained protein molecular dynamics simulations.

A limiting factor in biological science is the time-scale gap between experimental and computational trajectories. At this point, all-atom explicit solvent molecular dynamics (MD) are clearly too expensive to explore long-range protein motions and extract accurate thermodynamics of proteins in isolated or multimeric forms. To reach the appropriate time scale, we must then resort to coarse graining. Here we couple the coarse-grained OPEP model, which has already been used with activated methods, to MD simulations. Two test cases are studied: the stability of three proteins around their experimental structures and the aggregation mechanisms of the Alzheimer's Abeta16-22 peptides. We find that coarse-grained isolated proteins are stable at room temperature within 50 ns time scale. Based on two 220 ns trajectories starting from disordered chains, we find that four Abeta16-22 peptides can form a three-stranded beta sheet. We also demonstrate that the reptation move of one chain over the others, first observed using the activation-relaxation technique, is a kinetically important mechanism during aggregation. These results show that MD-OPEP is a particularly appropriate tool to study qualitatively the dynamics of long biological processes and the thermodynamics of molecular assemblies.

Amyloid beta-Peptides↗
PubMed1994

Lagrangian molecular dynamics using selected conformational degrees of freedom, with application to the pseudorotation dynamics of furanose rings.

Using internal conformational degrees of freedom for biopolymers as natural variables, and introducing a Lagrangian dynamics approach, one can simulate time-dependent processes over a much longer time scale than in classical Newtonian molecular dynamics (MD) techniques. Two factors contribute to this: a substantial reduction in the number of degrees of freedom and a very large increase in the size of the time step. We present the Lagrangian equations of motion for repuckering transitions in model furanose (F), ribose (R), and 2'-deoxyribose (dR) ring systems using the pseudorotation phase angle as the single dynamic variable. As in most Lagrangian analyses, the effective masses for the R and dR models are dependent on conformation, and we test the behavior of this variable mass (VM) model. Since the variation in effective mass is small, the VM model is compared with a simplified constant mass (CM) model, which is shown to be an excellent approximation. The equations of motion for the CM and VM models are integrated with the leapfrog and the iterative leapfrog algorithms, respectively. The Lagrangian dynamics approach reduces the number of degrees of freedom from about 40 to 1, and allows the use of time steps on the order of 20 fs, about an order of magnitude greater than is used in conventional MD simulations.

Biopolymers↗
PubMed2006

The sequence-dependent unfolding pathway plays a critical role in the amyloidogenicity of transthyretin.

Human transthyretin (TTR) is an amyloidogenic protein whose aggregation is associated with several types of amyloid diseases. The following mechanism of TTR amyloid formation has been proposed. TTR tetramer at first dissociates into native monomers, which is the rate-limiting step in fibril formation. The monomeric species then partially unfold to form amyloidogenic intermediates that subsequently undergo a downhill self-assembly process. The amyloid deposit can be facilitated by disease-associated point mutations. However, only subtle structural differences were observed between the crystal structures of the wild type and the disease-associated variants. To investigate how single-point mutations influence the effective energy landscapes of TTR monomers, molecular dynamics (MD) simulations were performed on wild-type TTR and two pathogenic variants. Principal coordinate analysis on MD-generated ensembles has revealed multiple unfolding pathways for each protein. Amyloidogenic intermediates with the dislocated C strand-loop-D strand motif were observed only on the unfolding pathways of V30M and L55P variants and not for wild-type TTR. Our study suggests that the sequence-dependent unfolding pathway plays a crucial role in the amyloidogenicity of TTR. Analyses of side chain concerted motions indicate that pathogenic mutations on "edge strands" disrupt the delicate side chain correlated motions, which in turn may alter the sequence of unfolding events.

Amyloid↗
PubMed2002

The secret of dimethyl sulfoxide-water mixtures. A quantum chemical study of 1DMSO-nwater clusters.

DMSO-water mixtures exhibit a marked freezing point depression, reaching close to 60 K at n(DMSO) = 0.33. The phase diagram indicates that stable DMSO-water clusters may be responsible for this phenomenon. Using time-independent quantum chemical methods, we investigate possible candidates for stable supermolecules at mole fractions n(DMSO) = 0.25 and 0.33. The model clusters are built by adding various numbers of water molecules to a single DMSO molecule. Structures and interaction energetics are discussed in the light of experimental and theoretical results from the literature. A comparison with results from molecular dynamics simulations is of particular interest. Our optimized structures are spatially very different from those previously identified through MD simulations. To identify the structural patterns characterizing the clusters, we classify them on the basis of hydrogen-acceptor interactions. These are well separated on an interaction energy scale. For the hydrophobic interactions of the methyl groups with water, attractive interactions of up to 8 kJ/mol are found. In forming clusters corresponding to a range of different mole fractions, up to four water molecules are added to each DMSO molecule. This corresponds to a rough local model of solvation. Examination of the trends in the interactions indicates that the methyl-water interaction becomes more important upon solvation. Finally, we investigate how the clusters interact and attempt to explain which role is played by the various structures and their intercluster interaction modes in the freezing behavior of DMSO-water.

Journal Article↗
PubMed2004

Ligand intramolecular motions in ligand-protein interaction: ALPHA, a novel dynamic descriptor and a QSAR study with extended steroid benchmark dataset.

The role of intramolecular motions in ligand-macromolecule interactions has been explored by developing and validating ALPHA, a novel QSAR (quantitative structure-activity relationship) descriptor. It is based on the spectral exponents (alpha), which measure the degree of 1/f alpha noise of coordinate fluctuations in molecular dynamics (MD) simulations. ALPHA is the first truly 'dynamic' QSAR descriptor, i.e., it can be derived directly from an MD trajectory. The performance of ALPHA was tested in detail employing the CBG (corticosteroid binding globulin) affinity of 31 benchmark steroids, supplemented with 11 steroids as an external test set. The only fair (42-50%) correlations of ALPHA with static 3D and electronic descriptors mean that ALPHA forms an independent molecular property. Furthermore, inclusion of ALPHA in the SOMFA/ESP model improves the correlation coefficient from 0.86 to 0.91, and /delta/ave from 0.46 to 0.36 for the benchmark dataset. The predictive ability of ALPHA can be interpreted as indirect evidence of the dynamic contribution to ligand-macromolecule interactions. The physical background of ALPHA is discussed and the importance of molecular motions for biological activity is anticipated.

Ligands↗
PubMed2006

Prediction of viscosity for molecular fluids at experimentally accessible shear rates using the transient time correlation function formalism.

Nonequilibrium molecular dynamics (NEMD) simulations were performed and the transient time correlation function (TTCF) method applied to calculate the shear viscosity of n-decane. Using the TTCF method we were able to calculate the viscosity at shear rate orders of magnitude lower than is possible by direct NEMD simulation alone. For the first time for a molecular fluid, we were able to simulate shear rates accessible by experimental measurements, which are typically performed at shear rates well below those accessible by NEMD simulation. The TTCF method allows us to close the gap between the lowest shear rates accessible by MD simulation and the highest shear rates possible in experimental studies. Additionally a multiple time step method for Gaussian thermostatted SLLOD equations of motion was developed following earlier work [G. A. Pan et al., J. Chem. Phys. 122, 4114 (2005)] for atomic fluids.

Journal Article↗
PubMed2004

Ab initio molecular dynamics simulations and g-tensor calculations of aqueous benzosemiquinone radical anion: effects of regular and "T-stacked" hydrogen bonds.

Car-Parrinello molecular dynamics (CP-MD) simulations of the benzosemiquinone radical anion in aqueous solution have been performed at ambient conditions. Analysis of the trajectory shows not only extensive hydrogen bonding to the carbonyl oxygen atoms (ca. 4-5.6 water molecules depending on distance criteria), but also relatively long-lived "T-stacked" hydrogen bonds to the semiquinone pi-system. These results are discussed in the context of recent findings on semiquinone-protein interactions in photosynthetic reaction centers, and of EPR and vibration spectroscopical data for the aqueous system. Snapshots from the CP-MD trajectory are used for the first quantum chemical analyses of dynamical effects on electronic g-tensors, using cluster models and a recently developed density functional method. In particular, the effects of intermolecular hydrogen-bond dynamics on the g-tensor components are examined, in comparison with recent EPR and ENDOR studies.

Benzoquinones↗
PubMed2006

Water-silica force field for simulating nanodevices.

Amorphous silica is an inorganic material that is central for many nanotechnology applications, such as nanoelectronics, microfluidics, and nanopore sensors. To use molecular dynamics (MD) simulations to study the behavior of biomolecules interacting with silica, we developed a force field for amorphous silica surfaces based on their macroscopic wetting properties that is compatible with the CHARMM force field and TIP3P water model. The contact angle of a water droplet on a silica surface served as a criterion to tune the intermolecular interactions. The resulting force field was used to study the permeation of water through silica nanopores, illustrating the influence of the surface topography and the intermolecular parameters on permeation kinetics. We find that minute modeling of the amorphous surface is critical for MD studies, since the particular arrangement of surface atoms controls sensitively electrostatic interactions between silica and water.

Nanostructures↗