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At least 253 records · Page 14Linked to original sources

PubMed1998

Solution structure of a syndecan-4 cytoplasmic domain and its interaction with phosphatidylinositol 4,5-bisphosphate.

Syndecan-4, a transmembrane heparan sulfate proteoglycan, is a coreceptor with integrins in cell adhesion. It has been suggested to form a ternary signaling complex with protein kinase Calpha and phosphatidylinositol 4,5-bisphosphate (PIP2). Syndecans each have a unique, central, and variable (V) region in their cytoplasmic domains, and that of syndecan-4 is critical to its interaction with protein kinase C and PIP2. Two oligopeptides corresponding to the variable region (4V) and whole domain (4L) of syndecan-4 cytoplasmic domain were synthesized for nuclear magnetic resonance (NMR) studies. Data from NMR and circular dichroism indicate that the cytoplasmic domain undergoes a conformational transition and forms a symmetric dimer in the presence of phospholipid activator PIP2. The solution conformations of both free and PIP2-complexed 4V have been determined by two-dimensional NMR spectroscopy and dynamical simulated annealing calculations. The 4V peptide in the presence of PIP2 formed a compact dimer with two twisted strands packed parallel to each other and the exposed surface of the dimer consisted of highly charged and polar residues. The overall three-dimensional structure in solution exhibits a twisted clamp shape having a cavity in the center of dimeric interface. In addition, it has been observed that the syndecan-4V strongly interacts not only with fatty acyl groups but also the anionic head group of PIP2. These findings reveal that PIP2 promotes oligomerization of syndecan-4 cytoplasmic domain for transmembrane signaling and cell-matrix adhesion.

Amino Acid Sequence↗

PubMed2005

A complete mock circulation loop for the evaluation of left, right, and biventricular assist devices.

A new mock circulation loop was developed to replicate the necessary features of the systemic and pulmonic circulatory systems, including pulsatile left and right ventricles coupled with vascular compliances and resistances. A brief description of the mock loop construction is provided before results are presented confirming the recreation of perfusion rates and pressures found in the natural systemic and pulmonic vascular trees for a normal and failing heart at rest. This rig provides the ability to evaluate the hemodynamic effect of left, right, and biventricular assist devices in vitro. The small and compact mock circulation rig has the potential to reduce device evaluation costs by simulating the natural circulatory system, thus providing valuable device performance feedback prior to expensive in vivo animal trials.

Blood Circulation↗

PubMed2006

Sampling realistic protein conformations using local structural bias.

The prediction of protein structure from sequence remains a major unsolved problem in biology. The most successful protein structure prediction methods make use of a divide-and-conquer strategy to attack the problem: a conformational sampling method generates plausible candidate structures, which are subsequently accepted or rejected using an energy function. Conceptually, this often corresponds to separating local structural bias from the long-range interactions that stabilize the compact, native state. However, sampling protein conformations that are compatible with the local structural bias encoded in a given protein sequence is a long-standing open problem, especially in continuous space. We describe an elegant and mathematically rigorous method to do this, and show that it readily generates native-like protein conformations simply by enforcing compactness. Our results have far-reaching implications for protein structure prediction, determination, simulation, and design.

Amino Acid Sequence↗

PubMed2004

Novel force resolver designs for a haptic surgery simulator.

This paper presents the results of an investigation into the design of low cost, four degree of freedom force/torque resolvers for use in compact haptic devices for surgical training. Two designs using piezo-resistive sensors are described and one using strain gauges. The advantages and disadvantages of each approach are stated and conclusions presented.

Computer Simulation↗

PubMed1999

Bioactivity of pseudowollastonite in human saliva.

OBJECTIVES: Pseudowollastonite (CaO.SiO2) was found to be bioactive in a simulated body fluid environment. In the present study, 'in vitro' bioactivity of pseudowollastonite was further assessed in human parotid saliva. The main objective was to compare behaviour of the material in a natural medium of high protein content (human parotid saliva) with its behaviour in an acellular protein-free solution (simulated body fluid). METHODS: Samples of polycrystalline pseudowollastonite were immersed for one month in human parotid saliva at 37 degrees C. Changes in ionic concentrations in the human parotid saliva and the pH right at the interface of pseudowollastonite/human parotid saliva were determined. The products of the interfacial reactions were studied by thin-film X-ray diffraction, scanning and transmission electron microscopy. RESULTS: The results confirmed formation of a hydroxyapatite-like layer on the surface of the material, and also suggested that the mechanism of hydroxyapatite-like layer formation in saliva was similar to that showed in simulated body fluid. CONCLUSIONS: The hydroxyapatite-like layer formed at the interface was found to be compact, continuous and composed of many small crystallites with ultrastructure similar to that of natural cortical bone and dentine. The study also concluded that the high pH conditions (10.32) existing right at the pseudowollastonite/human parotid saliva interface promoted hydroxyapatite-like precipitation. At this stage of the study, similarities of the material behaviour in saliva and acellular simulated body fluid suggest that the pseudowollastonite could be of interest in specific periodontal applications for bone restorative purposes.

Body Temperature↗

PubMed2004

Long-term prediction of three-dimensional bone architecture in simulations of pre-, peri- and post-menopausal microstructural bone remodeling.

The mechanical behavior of trabecular bone depends on the internal bone structure. It is generally accepted now that the trabecular bone structure is a result of a load adaptive bone remodeling. The mathematical laws that relate bone remodeling to the local state of stress and strain, however, are still under investigation. The aim of this project was to investigate if changes in the trabecular architecture as observed with age-related bone loss and osteoporosis can be predicted from a computer model that simulates bone resorption after hormone depletion based on realistic models of trabecular microstructure using micro-computed tomography (muCT). A compact desktop muCT providing a nominal isotropic resolution of 14 mum was used to measure two groups of seven trabecular bone specimens from pre-menopausal and post-menopausal women respectively. A novel algorithm was developed to simulate age-related bone loss for the specimens in the first group. The algorithm, also referred to as simulated bone atrophy (SIBA), describes a truly three-dimensional approach and is based directly on cellular bone remodeling with an underlying realistic time frame. Bone resorption is controlled by osteoclastic penetration depth and bone formation is governed by the efficiency level of the osteoblasts. The simulation itself describes an iterative process with a cellular remodeling cycle of 197 days. Activation frequency is controllable and can be adjusted for the different phases of pre-, peri- and post-menopause. For our simulations, osteoblastic and osteoclastic activities were in balance until the onset of menopause, set to be at the age of 50 years. In that period, the structure remained almost constant. After the onset of menopause an imbalance in the cell activities was modeled resulting in a net bone loss. The doubling of the activation frequency in the peri-menopausal phase caused a pronounced loss. Using advanced animation tools and quantitative bone morphometry, the changes in bone architecture associated with the bone loss were monitored over an average observation time of 43 years until the age of 80 years. In that time, bone volume density decreased monotonously with the progression of the simulation for all specimens. Right after the onset of menopause, bone was lost fast, where with the progression of age losses slowed down. The structures at the end-point of the simulations were then compared qualitatively and quantitatively to the structures of the post-menopausal group with all morphometric indices being within a narrow margin of error. These results suggest the feasibility of transforming "normal" to "osteopenic" bone on a microstructural level yielding in realistic bone models similar in appearance as well as in structural behavior if compared to a post-menopausal group of women.

Aged↗

PubMed2004

A molecular dynamics study of Ca(2+)-calmodulin: evidence of interdomain coupling and structural collapse on the nanosecond timescale.

A 20-ns molecular dynamics simulation of Ca(2+)-calmodulin (CaM) in explicit solvent is described. Within 5 ns, the extended crystal structure adopts a compact shape similar in dimension to complexes of CaM and target peptides but with a substantially different orientation between the N- and C-terminal domains. Significant interactions are observed between the terminal domains in this compact state, which are mediated through the same regions of CaM that bind to target peptides derived from protein kinases and most other target proteins. The process of compaction is driven by the loss of helical structure in two separate regions between residues 75-79 and 82-86, the latter being driven by unfavorable electrostatic interactions between acidic residues. In the first 5 ns of the simulation, a substantial number of contacts are observed between the first helix of the N-terminal domain and residues 74-77 of the central linker. These contacts are correlated with the closing of the second EF-hand, indicating a mechanism by which they can lower calcium affinity in the N-terminal domain.

Binding Sites↗

PubMed1992

A model of the molten globule state from molecular dynamics simulations.

It is generally accepted that a protein's primary sequence determines its three-dimensional structure. It has proved difficult, however, to obtain detailed structural information about the actual protein folding process and intermediate states. We present the results of molecular dynamics simulations of the unfolding of reduced bovine pancreatic trypsin inhibitor. The resulting partially "denatured" state was compact but expanded relative to the native state (11-25%); the expansion was not caused by an influx of water molecules. The structures were mobile, with overall secondary structure contents comparable to those of the native protein. The protein experienced relatively local unfolding, with the largest changes in the structure occurring in the loop regions. A hydrophobic core was maintained although packing of the side chains was compromised. The properties displayed in the simulation are consistent with unfolding to a molten globule state. Our simulations provide an in-depth view of this state and details of water-protein interactions that cannot yet be obtained experimentally.

Animals↗

PubMed2004

The unfolding action of GroEL on a protein substrate.

A molecular dynamics simulation of the active unfolding of denatured rhodanese by the chaperone GroEL is presented. The compact denatured protein is bound initially to the cis cavity and forms stable contacts with several of the subunits. As the cis ring apical domains of GroEL undergo the transition from the closed to the more open (ATP-bound) state, they exert a force on rhodanese that leads to the increased unfolding of certain loops. The contacts between GroEL and rhodanese are analyzed and their variation during the GroEL transition is shown. The major contacts, which give rise to the stretching force, are found to be similar to those observed in crystal structures of peptides bound to the apical domains. The results of the simulation show that multidomain interactions play an essential role, in accord with experiments. Implications of the results for mutation experiments and for the action of GroEL are discussed.

Binding Sites↗

PubMed1999

Bead compacts. II. Evaluation of rapidly disintegrating nonsegregating compressed bead formulations.

In this study, three techniques for the prevention or mitigation of polymer coat fracture on compaction of sustained-release beads into tablets were investigated. All techniques in this paper were evaluated without the addition of any cushioning excipients, but rather by spray coating these excipients to avoid segregation during product manufacturing. First, it was shown that use of swellable polymers such as polyethylene oxide (PEO) serves a unique and effective role in preventing polymer coat rupture. PEO was spray coated between the ethylcellulose (EC) and microcrystalline cellulose (MCC) coats to evaluate its cushioning effect. The compacted PEO layered beads, on dissolution, disintegrated into individual beads with sustained drug release of up to 8 hr. It is postulated that the PEO was hydrated and formed a gel that acts as a sealant for the cracks formed in the ruptured polymer coating (sealant-effect compacts). Second, EC-coated drug-layered beads were also overcoated with cushioning excipients such as polyethylene glycol (PEG) and MCC with an additional coating of a disintegrant. These beads were compressed at pressures of 125, 500, and 1000 pounds into caplets and, on dissolution testing, disintegrated into individual beads when the dissolution medium was switched from simulated gastric to intestinal fluid. The dissolution profiles show that the polymer coat was partly disrupted on compaction, leading to a total drug release in 8-10 hr. Third, EC-coated beads were also granulated with cushioning excipient and compressed.

Chemistry, Pharmaceutical↗

PubMed2006

Potential influence of Asp in the Ca2+ coordination position 5 of parvalbumin on the calcium-binding affinity: a computational study.

Parvalbumins (PV) are calcium-binding proteins, all sharing the common helix-loop-helix (EF-hand) motif. This motif contains a central twelve-residue Ca(2+)-binding loop with the flanking helices positioned roughly perpendicular to each other. The precise role of these coordination residues has been the subject of intense studies. In this work, we focus on the coordination position 5 in the CD Ca(2+)-binding site of silver hake parvalbumin isoform B (SHPV-B). The most common residue at site 5 of calcium-binding loop in canonical EF-hands is Asp [B.J. Marsden, G.S. Shaw, B.D. Sykes, Biochem. Cell Biol. 68 (1990) 587-601], but in the CD site of PV, this position is almost always serine (Ser). The substitution of Ser with Asp will add the 5th carboxylate residue in the CD coordination sphere. However, as predicted by the acid pair hypothesis, the Ca(2+)-binding affinity would be maximized in an EF-hand motif that has four carboxylate ligands paired along the +/-x, and +/-z-axes [R.E. Reid, R.S. Hodges, J. Theor. Biol. 84 (1980) 401-444]. Molecular dynamics simulations and free energy calculations were employed to investigate the influence of Ser to Asp mutation at position 5 on calcium-binding affinity. We found that the Asp variant exhibited remarkable stability during the entire molecular dynamics simulation, with not only the retention of the Ca(2+)-binding site, but also increased compactness in the coordination sphere. The S55D fragment also accommodated Ca(2+) well. We conclude that the reason why Asp which is the most common residue at site 5 of calcium-binding loop in canonical EF-hands has never been identified at this position experimentally for PVs might be related to its physiological functions.

Amino Acid Sequence↗

PubMed2005

Corrosion behavior of Cu and the Cu-Zn-Al shape memory alloy in simulated uterine fluid.

Chemical immersion tests, electrochemical methods and atomic absorption spectrometry were employed to investigate the corrosion behavior of Cu and the Cu-Zn-Al shape memory alloy (SMA) in simulated uterine fluid. The effect of pH on corrosion rate and corrosion potential was also investigated. The results indicated that in the static state in simulated uterine fluid, dealuminumification of the Cu-Zn-Al alloy occurred with Cl- combining with aluminum ions to form hydroxyl aluminum chloride. The hydroxyl aluminum chloride hydrolyzed readily and facilitated further dealuminumification corrosion. The corrosion process of Cu and Cu-Zn-Al SMA in simulated uterine fluid was controlled by cathodic reduction of oxygen. Because the tendency for surface ionization is greater for aluminum than for zinc, a compact protective aluminum layer was formed, which inhibited the cathodic reduction of oxygen. Hence, the corrosion rate of Cu-Zn-Al SMA was smaller than that of Cu in simulated uterine fluid. With increasing pH, the corrosion rate of Cu and Cu-Zn-Al SMA in simulated uterine fluid decreased and the open-circuit potential moved in a positive direction.

Alloys↗

PubMed1999

Effect of artificial periodicity in simulations of biomolecules under Ewald boundary conditions: a continuum electrostatics study.

Ewald and related methods are nowadays routinely used in explicit-solvent simulations of biomolecules, although they impose an artificial periodicity in systems which are inherently non-periodic. The consequences of this approximation should be assessed, since they may crucially affect the reliability of computer simulations under Ewald boundary conditions. In the present study we use a method based on continuum electrostatics to investigate the nature and magnitude of possible periodicity-induced artifacts on the potentials of mean force for conformational equilibria in biomolecules. Three model systems and pathways are considered: polyalanine oligopeptides (unfolding), a DNA tetranucleotide (separation of the strands), and the protein Sac7d (conformations from a molecular dynamics simulation). Artificial periodicity may significantly affect these conformational equilibria, in each case stabilizing the most compact conformation of the biomolecule. Three factors enhance periodicity-induced artifacts: (i) a solvent of low dielectric permittivity; (ii) a solute size which is non-negligible compared to the size of the unit cell; and (iii) a non-neutral solute. Neither the neutrality of the solute nor the absence of charge pairs at distances exceeding half the edge of the unit cell do guarantee the absence of artifacts.

Algorithms↗

PubMed1995

Functional role of arginine-11 in the N-terminal helix of skeletal troponin C: combined mutagenesis and molecular dynamics investigation.

The two main structural differences between calmodulin (CaM) and skeletal troponin C (sTnC) are the absence in CaM of (i) the short N-terminal helix in TnC and (ii) the triplet KGK (residues 91-93; numbering according to chicken sTnC). It was recently shown that deletion of both structural groups from sTnC imparted to the resulting construct the CaM-like ability to activate phosphodiesterase (PDE) and to regulate force development in smooth muscle. To continue probing of the structural basis of the differential behavior of sTnC and CaM, residue Arg-11 in rabbit sTnC was mutated to Ala because the interactions of Arg-11 with distal residues in the N-terminal domain seem to link the N-terminal helix to the rest of the structure. The mutant exhibits CaM-like function in its ability to activate PDE (about 50% of CaM at 5 microM concentration). If, in addition, the KGK triplet is also deleted, PDE activation increases to about 80%. Both constructs retain their TnC function to nearly 100%. To explore the mechanistic basis of this remarkable observation, computational simulations of the molecular dynamics (MD) were carried out for both wild-type 4Ca2+.sTnC and the 4Ca2+.R11A mutant, and the results were compared to those from earlier simulations of 4Ca2+.CaM. Two types of structural changes observed from such simulations of the molecular dynamics of CaM had been considered to have a functional role: (i) a compaction to a more globular form and (ii) a reorientation of the Ca-binding domains around the central tether helix.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed1999

Surface binding of alamethicin stabilizes its helical structure: molecular dynamics simulations.

Alamethicin is an amphipathic alpha-helical peptide that forms ion channels. An early event in channel formation is believed to be the binding of alamethicin to the surface of a lipid bilayer. Molecular dynamics simulations are used to compare the structural and dynamic properties of alamethicin in water and alamethicin bound to the surface of a phosphatidylcholine bilayer. The bilayer surface simulation corresponded to a loosely bound alamethicin molecule that interacted with lipid headgroups but did not penetrate the hydrophobic core of the bilayer. Both simulations started with the peptide molecule in an alpha-helical conformation and lasted 2 ns. In water, the helix started to unfold after approximately 300 ps and by the end of the simulation only the N-terminal region of the peptide remained alpha-helical and the molecule had collapsed into a more compact form. At the surface of the bilayer, loss of helicity was restricted to the C-terminal third of the molecule and the rod-shaped structure of the peptide was retained. In the surface simulation about 10% of the peptide/water H-bonds were replaced by peptide/lipid H-bonds. These simulations suggest that some degree of stabilization of an amphipathic alpha-helix occurs at a bilayer surface even without interactions between hydrophobic side chains and the acyl chain core of the bilayer.

Alamethicin↗

PubMed2002

Accuracy of recording horizontal condylar inclination and Bennett angle with the Cadiax compact.

This study assessed the accuracy of an electronic hinge axis tracing device (Cadiax compact) in measuring the horizontal condylar inclination (HCI) and the Bennett angle. The hinge axis movements were simulated with an articulator to which the hinge axis tracer was attached. On the articulator the pre-set HCI values were 20 degrees, 40 degrees and 60 degrees, the pre-set Bennett angles were 0 degrees, 5 degrees, 10 degrees, 15 degrees, 20 degrees. The maximum measuring errors ranged from 0 to 3.4 degrees (in average 1.2 degrees ) and yielded statistically significant differences between articulator setting and Cadiax compact measurement (P < 0.05) except the HCI of 40 degrees and the Bennett angle of 0 degrees. Because of the small range of the maximum measuring error the Cadiax compact represented reasonable accuracy for clinical application in anterior guidance restorations.

Anthropometry↗

PubMed2003

Structural fitting of PISEMA spectra of aligned proteins.

An algorithm for fitting protein structures to PISEMA spectra is described, and its application to helical proteins in aligned samples is demonstrated using both simulated and experimental results. The formulation of the algorithm in terms of rotation operators yields compact recursion relations that provide a fast and effective way of obtaining peptide plane orientations from chemical and torsion angle constraints. The algorithm in combination with experimental solid-state NMR data results in a method for determining the backbone structures of proteins, since it yields the orientation of a helix as a whole, including its tilt and twist angles, and describes kinks and curves with atomic resolution. Although the algorithm can be applied in an "assignment-free" manner to spectra of uniformly labeled proteins, the precision of the structural fitting is improved by the addition of assignment information, for example the identification of resonances by residue type from spectra of selectively labeled proteins.

Algorithms↗

PubMed1991

Prediction of the rotational diffusion behavior of biopolymers on the basis of their solution or crystal structure.

Two low structure-resolution methods are proposed for prediction of rotational diffusion parameters. The indirect procedure is based on the structure of a molecule in solution or in crystal, and uses the structure parameters of radius of gyration, and low-resolution molecular surface and volume, determined from measured or theoretically calculated small-angle x-ray scattering intensities, to estimate a frictional equivalent ellipsoid of revolution. The direct method starts mainly from the crystallographic structure of a molecule and calculates the triaxial inertia equivalent ellipsoid, experimentally calibrated by translation diffusion data, to simulate the frictional behavior. The predicted harmonic mean of the rotational correlation times of compact globular macromolecules with molar masses of 14,000-65,000 g/mol agree with experimental results within the error limits. The prediction method is recommended for expert systems in structure research and for detection of internal protein flexibility or marker mobility by nmr and electron paramagnetic resonance experiments.

Crystallography↗