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At least 325 records · Page 18Linked to original sources
PubMed1999

X-ray structure and conformational dynamics of the HIV-1 protease in complex with the inhibitor SDZ283-910: agreement of time-resolved spectroscopy and molecular dynamics simulations.

Based on the X-ray structure of the human immunodeficiency virus type-1 (HIV-1) protease in complex with the statine-derived inhibitor SDZ283-910, a 542 ps molecular dynamics trajectory was computed. For comparison with the 805 ps trajectory obtained for the uncomplexed enzyme, the theoretical fluorescence anisotropy decay of the unliganded protease and the inhibitor complex was calculated from the trajectories of the Trp6A/Trp6B and Trp42A/Trp42B transition dipole moments. This enabled us to directly compare the simulated data with the experimental picosecond time-resolved fluorescence data. Fitting both experimental and simulated data to the Kohlrausch-Williams-Watts (KWW) function exp(-t/tauk)beta revealed a very good agreement for the uncomplexed protease as well as for the SDZ283-910 complex. Binding of the inhibitor induced a faster decay of both the experimental and the computed protease fluorescence anisotropy decay. By this integrative approach, the atomic detail of inhibitor-induced changes in the conformational dynamics of the HIV-1 protease was experimentally verified and will be used for further inhibitor optimisation.

Anti-HIV Agents↗
PubMed1999

Structure, dynamics and hydration of the nogalamycin-d(ATGCAT)2Complex determined by NMR and molecular dynamics simulations in solution.

The structure of the 1:1 nogalamycin:d(ATGCAT)2 complex has been determined in solution from high-resolution NMR data and restrained molecular dynamics (rMD) simulations using an explicit solvation model. The antibiotic intercalates at the 5'-TpG step with the nogalose lying along the minor groove towards the centre of the duplex. Many drug-DNA nuclear Overhauser enhancements (NOEs) in the minor groove are indicative of hydrophobic interactions over the TGCA sequence. Steric occlusion prevents a second nogalamycin molecule from binding at the symmetry-related 5'-CpA site, leading to the conclusion that the observed binding orientation in this complex is the preferred orientation free of the complication of end-effects (drug molecules occupy terminal intercalation sites in all X-ray structures) or steric interactions between drug molecules (other NMR structures have two drug molecules bound in close proximity), as previously suggested. Fluctuations in key structural parameters such as rise, helical twist, slide, shift, buckle and sugar pucker have been examined from an analysis of the final 500 ps of a 1 ns rMD simulation, and reveal that many sequence-dependent structural features previously identified by comparison of different X-ray structures lie within the range of dynamic fluctuations observed in the MD simulations. Water density calculations on MD simulation data reveal a time-averaged pattern of hydration in both the major and minor groove, in good agreement with the extensive hydration observed in two related X-ray structures in which nogalamycin is bound at terminal 5'-TpG sites. However, the pattern of hydration determined from the sign and magnitude of NOE and ROE cross-peaks to water identified in 2D NOESY and ROESY experiments identifies only a few "bound" water molecules with long residence times. These solvate the charged bicycloaminoglucose sugar ring, suggesting an important role for water molecules in mediating drug-DNA electrostatic interactions within the major groove. The high density of water molecules found in the minor groove in X-ray structures and MD simulations is found to be associated with only weakly bound solvent in solution.

Base Sequence↗
PubMed1975

[Dynamics of manual stabbing tests. Contribution to the understanding of the "Outer stabbing dynamics" (author's transl)].

The following questions were considered: What were the manual stabbing-energies and -velocities achieved by test persons (50 men and 50 women); what was the sex specific difference in performance; were there differences between the "work-hand" and the "non-work-hand". Five single stabs were carried out with each hand. The impact-energy and the impact-velocity were measured for each stab. Significant differences were shown between the values of men and women, as well as between "work-hand" and "non-work-hand". For forensic purposes the "outer stabbing-dynamics"--demonstrated by the subject--can also be assessed in foro. The quantitative relations between stab-wound and necessary stabbing-energy and demonstrated "outer stabbing-dynamics" give an indication of the intention of the subject.

Biomechanical Phenomena↗
PubMed1989

A molecular dynamics study of the C-terminal fragment of the L7/L12 ribosomal protein. II. Effects of intermolecular interactions on structure and dynamics.

The crystallographic dimer of the C-terminal fragment (CTF) of the L7/L12 ribosomal protein has been subjected to molecular dynamics (MD) simulations. A 90 picosecond (ps) trajectory for the protein dimer, 19 water molecules and two counter ions has been calculated at constant temperature. Effects of intermolecular interactions on the structure and dynamics have been studied. The exact crystallographic symmetry is lost and the atomic fluctuations differ from one monomer to the other. The average MD structure is more stable than the X-ray one, as judged by accessible surface area and energy calculations. Crystal (non-dimeric) interactions have been simulated in another 40 ps trajectory by using harmonic restraints to represent intermolecular hydrogen bonds. The conformational changes with respect to the X-ray structure are then virtually suppressed. The unrestrained dimer trajectory has been scanned for cooperative motions involving secondary structure elements. The intrinsic collective motions of the monomer are transmitted via intermolecular contacts to the dimer structure. The existence of a stable dimeric form of CTF, resembling the crystallographic one, has been documented. At the cost of fairly small energy expenditure the dimer has considerable conformational flexibility. This flexibility may endow the dimer with some functional potential as an energy transducer.

Computer Simulation↗
PubMed1989

The dynamic properties of melittin in solution. Investigations by NMR and molecular dynamics.

Molecular dynamics simulations are described for the peptide melittin. The atomic trajectories are calculated both with normal potential energy functions and with additional distance restraints deduced from nuclear Overhauser effects observed in NMR experiments. The results are compared with NMR data on coupling constants and amide exchange rates and with B-factors from X-ray crystallography. The observed correlations between experiment and molecular dynamics simulations suggest a relatively mobile C-terminus and relatively high flexibility around residue 11. It is noted that the high conformational variation around residue 11 is due in part to the presence of a proline at position 14 which results in a "missing" H-bond in the largely alpha-helical structure. It is also noted that a proline is a common feature of many putative membrane spanning helices. A role for such prolines is suggested.

Bee Venoms↗
PubMed1987

Molecular dynamics simulations of cyclosporin A: the crystal structure and dynamic modelling of a structure in apolar solution based on NMR data.

The conformation of the immunosuppressive drug cyclosporin A (CPA), both in apolar solution and in crystalline state, has been studied by computer simulation techniques. Three molecular dynamics (MD) simulations have been performed: one modelling the crystal structure and two modelling the structure in apolar solution, using a restrained MD approach in which data from nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy are taken into account. The simulation of the crystalline state (MDC) concerns a system of 4 unit cells containing 16 cyclosporin A molecules and 22 water molecules, which is simulated using crystalline periodic boundary conditions. The simulations modelling the apolar solvent conformation (MDS) concern one isolated cyclosporin A molecule. In these simulations an extra term in the interatomic potential function is used, which forces the molecule to satisfy a set of 57 atom-atom distance constraints originating from nuclear Overhauser effects (NOEs) obtained from NMR spectroscopy and one distance constraint deduced from IR spectroscopy. From a comparison of the results of the crystal simulation to those of the X-ray experiment in terms of structure, atomic fluctuations, hydrogen bond pattern, etc., it is concluded that the force field that is used yields an adequate representation of crystalline cyclosporin A. Secondly, it is shown that the dynamic modelling technique that is used to obtain a structure in a polar solution from NMR distance information works well. Starting from initial conformations which have a root mean square difference of 0.14 nm both distance restrained MD simulations converge to the same final solution structure. A comparison of the crystal structure of cyclosporin A and the one in apolar solution shows that there are significant differences. The overall difference in atomic positions is 0.09 nm for the C alpha atoms and 0.17 nm for all atoms. In apolar solution, the molecule is slightly more bent and the side chains of 1 MeBmt and 10 MeLeu adopt a different conformation.

Computer Simulation↗
PubMed1992

Dynamic properties of salmon calcitonin bound to sodium dodecyl sulfate micelles: a restrained molecular dynamics study from NMR data.

We have investigated the conformational behaviour of salmon calcitonin bound to sodium dodecyl sulfate micelles by means of restrained molecular dynamics simulations with both 'static' and time-averaged NMR distance restraints. A more realistic picture of the inherent flexibility of the hormone is obtained when using time averaging. With this approach, long-range NOEs are interpreted better by considering a dynamical exchange among different conformations.

Amino Acid Sequence↗
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↗
PubMed2003

Implant-related complications in the treatment of unstable intertrochanteric fractures: meta-analysis of dynamic screw-plate versus dynamic screw-intramedullary nail devices.

The choice between dynamic screw-intramedullary nail (DSIN) devices and dynamic screw-plate (DSP) devices for the fixation of unstable trochanteric fractures remains controversial. This study presents a meta-analysis of fixation failures in unstable trochanteric femoral fractures using DSP devices or DSIN devices. Two independent assessors selected randomised controlled trials using a range of electronic databases, as well as reference lists of selected articles. A study quality checklist was used. The occurrence of fixation failure, in particular cut-out, was the primary subject of analysis using descriptive statistics and random-effect meta-analyses. Seventeen trials were identified. Meta-analyses showed no significant difference in the frequency of implant-related complications between the two types of devices. Iatrogenic femoral fractures associated with the use of DSIN devices represent a rare, but persistent, risk. There was a tendency for less frequent cut-out with intramedullary devices compared with DSP devices.

Bone Nails↗
PubMed2004

Dynamic echo-planar MR imaging of the diaphragm for a 3D dynamic analysis.

The purpose of this study was to prove the feasibility of 3D reconstructions of the diaphragm during the respiratory cycle using EPI sequences (EPI acquisition, 270 ms/image, on a healthy subject breathing spontaneously and at 0.1 Hz). Continuously recorded respiratory signal allowed for retrospective synchronization with respiratory phases for reconstruction of successive diaphragm surfaces using a specifically designed software. Displacements, area and volume changes of the diaphragm were quantified. Our measurements were comparable with the data in the literature. Reconstructed surfaces allowed in vivo diaphragm dynamic evaluation in terms of displacements, area and volume variations. EPI has adequate spatial and temporal resolution for studying diaphragm dynamics during natural breathing.

Diaphragm↗
PubMed2004

Tear flow dynamics in the human nasolacrimal ducts--a pilot study using dynamic magnetic resonance imaging.

BACKGROUND: Jones's theory of tear drainage suggests that the lacrimal sac fills when the eyelids are closed and empties into the nasolacrimal duct when the eyelids are open. This is aided by the contraction of the orbicularis muscle during each blink. This study was undertaken to ascertain the possibility of seeing the dynamic movement of tears in the nasolacrimal system during blinks using magnetic resonance dacryocystography (MR-DCG). METHODS: The sac was initially localized with a three-plane gradient echo sequence using a 1.5-T MRI platform. Fast, dynamic MR-DCG was carried out after we had instilled topically balanced salt solution (BSS) in five subjects and 0.5% gadolinium in seven subjects. The volunteers were asked to close and open their eyes during the fast imaging. The images were digitized to enable us to see the actual movement of fluid in the system. RESULTS: The tear movement was clearly seen as a bolus in the volunteers where BSS was used. The fluid passed into the nasolacrimal duct after several blinks when patent. The sac was never seen to empty completely. Though differential filling was seen between the upper and lower part of the sac, it was difficult to see the actual fluid movement in the volunteers when topical gadolinium was used. CONCLUSION: The findings of the study are supportive of the notion of fluid travel in the form of a bolus through the sac. Once a threshold volume is reached in the lower end of the sac, the fluid is seen to pass through the nasolacrimal duct. This happens after several blinks.

Acetates↗
PubMed2005

Myofascial force transmission in dynamic muscle conditions: effects of dynamic shortening of a single head of multi-tendoned rat extensor digitorum longus muscle.

This study investigated the effects of myofascial force transmission during dynamic shortening of head III of rat extensor digitorum longus muscle (EDL III). The anterior crural compartment was left intact. Force was measured simultaneously at the distal EDL III tendon, the proximal EDL tendon and the distal tendons of tibialis anterior and extensor hallucis longus muscles (TA + EHL). Two types of distal shortening of EDL III were studied: (1) sinusoidal shortening (2 mm) and (2) isokinetic shortening (8 mm). Sinusoidal shortening of EDL III caused a decrease in force exerted at the distal tendon of EDL III: from 0.58 (0.08) N to 0.26 (0.04) N. In contrast, hardly any changes in proximal EDL force and distal TA+EHL force were found. Maximal concentric force exerted at the distal tendon of EDL III was higher than maximal isometric force expected on the basis of the physiological cross-sectional area of EDL III muscle fibers (Maas et al. 2003). Therefore, a substantial fraction of this force must originate from sources other than muscle fibers of EDL III. Isokinetic shortening of EDL III caused high changes in EDL III force from 0.97 (0.15) N to zero. In contrast, changes in proximal EDL force were much smaller: from 2.44 (0.25) N to 1.99 (0.19) N. No effects on TA + EHL force could be shown. These results are explained in terms of force transmission between the muscle belly of EDL III and adjacent tissues. Thus, also in dynamic muscle conditions, muscle fiber force is transmitted via myofascial pathways.

Animals↗
PubMed2002

Mesoscopic dynamics of colloids simulated with dissipative particle dynamics and fluid particle model.

We report results of numerical simulations of complex fluids, using a combination of discrete-particle methods. Our molecular modeling repertoire comprises three simulation techniques: molecular dynamics (MD), dissipative particle dynamics (DPD), and the fluid particle model (FPM). This type of model can depict multi-resolution molecular structures found in complex fluids ranging from single micelle, colloidal crystals, large-scale colloidal aggregates up to the mesoscale processes of hydrodynamical instabilities in the bulk of colloidal suspensions. We can simulate different colloidal structures in which the colloidal beds are of comparable size to the solvent particles. This undertaking is accomplished with a two-level discrete particle model consisting of the MD paradigm with a Lennard-Jones (L-J) type potential for defining the colloidal particle system and DPD or FPM for modeling the solvent. We observe the spontaneous emergence of spherical or rod-like micelles and their crystallization in stable hexagonal or worm-like structures, respectively. The ordered arrays obtained by using the particle model are similar to the 2D colloidal crystals observed in laboratory experiments. The micelle shape and its hydrophobic or hydrophilic character depend on the ratio between the scaling factors of the interactions between colloid-colloid to colloid-solvent. Unlike the miscellar arrays, the colloidal aggregates involve the colloid-solvent interactions prescribed by the DPD forces. Different from the assumption of equilibrium growth, the two-level particle model can display much more realistic molecular physics, which allows for the simulation of aggregation for various types of colloids and solvent liquids over a very broad range of conditions. We discuss the potential prospects of combining MD, DPD, and FPM techniques in a single three-level model. Finally, we present results from large-scale simulation of the Rayleigh-Taylor instability and dispersion of colloidal slab in 2D and 3D. Electronic supplementary material to this paper can be obtained by using the Springer LINK server located at http://dx.doi.org/10.1007/s00894-001-0068-3.

Colloids↗
PubMed2006

Computerized methods for determining respiratory phase on dynamic chest radiographs obtained by a dynamic flat-panel detector (FPD) system.

Chest radiography using a dynamic flat-panel detector with a large field of view can provide sequential chest radiographs during respiration. These images provide information regarding respiratory kinetics, which is effective for diagnosis of pulmonary diseases. For valid analysis of respiratory kinetics in diagnosis of pulmonary diseases, it is crucial to determine the association between the kinetics and respiratory phase. We developed four methods to determine the respiratory phase based on image information associated with respiration and compared the results in dynamic chest radiographs of 37 subjects. Here, the properties of each method and future tasks are discussed. The method based on the change in size of the lung gave the most stable results, and that based on the change in distance from the lung apex to the diaphragm was the most promising method for determining the respiratory phase.

Humans↗
PubMed1987

Protein dynamics. A time-resolved fluorescence, energetic and molecular dynamics study of ribonuclease T1.

Studies using time-resolved fluorescence depolarization were performed on the internal motion of Trp 59 of ribonuclease T1 (EC 3.1.27.3) in the free enzyme, 2'-GMP-enzyme complex and 3'-GMP-enzyme complex. The Trp 59 motion was also studied in the free enzyme using molecular dynamics simulations. Energetic analysis of activation barriers to the Trp 59 motion was performed using both the transition state theory and Kramers' theory. The activation parameters showed a dependence on solvent viscosity indicating the transition state approach in aqueous solution to be inadequate. When taking solvent viscosity contributions into account agreement between the transition state and Kramers' theories was obtained. The results indicate the three enzyme forms to have different conformations with the free enzyme and 3'-GMP-enzyme complex being similar. Comparison of the experimental and theoretical results showed a good agreement on the Trp 59 motion in the free enzyme. Trp 59 appears to vibrate rapidly, with a relaxation time of the order of 1 ps, within free space in the protein matrix and to have a slower motion, with a relaxation time of the order of 100 ps, which is related to breathing of the surrounding protein matrix. Molecular dynamics results indicate high mobility in regions of the enzyme involved in the interaction with the guanine base of the inhibitor or substrate while much lower mobility occurred in residues involved in the catalytic mechanism of ribonuclease T1.

Aspergillus oryzae↗
PubMed1989

Configurational and dynamic properties of different length superhelical DNAs measured by dynamic light scattering.

The solution conformation and internal motions of five superhelical DNAs between 2100 and 10200 base-pairs in length have been characterized by dynamic light scattering (DLS). Variations in the diffusion coefficients and rotational relaxation times with molecular weight are both indicative of an anisotropic extended structure of these DNAs; we therefore conclude that under our conditions the interwound superhelical structure prevails. The internal dynamics can be described by a superposition of rotational diffusion and internal relaxation. The latter process is characterized by the internal diffusion of persistence length size segments within the DNA chain and faster bending motions within these segments.

Chemical Phenomena↗