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PubMed2005

Cofilin increases the torsional flexibility and dynamics of actin filaments.

We have measured the effects of cofilin on the conformation and dynamics of actin filaments labeled at Cys374 with erythrosin-iodoacetemide (ErIA), using time-resolved phosphorescence anisotropy (TPA). Cofilin quenches the phosphorescence intensity of actin-bound ErIA, indicating that binding changes the local environment of the probe. The cofilin concentration-dependence of the phosphorescence intensity is sigmoidal, consistent with cooperative actin filament binding. Model-independent analysis of the anisotropies indicates that cofilin increases the rates of the microsecond rotational motions of actin. In contrast to the reduction in phosphorescence intensity, the changes in the rates of rotational motions display non-nearest-neighbor cooperative interactions and saturate at substoichiometric cofilin binding densities. Detailed analysis of the TPA decays indicates that cofilin decreases the torsional rigidity (C) of actin, increasing the thermally driven root-mean-square torsional angle between adjacent filament subunits from approximately 4 degrees (C = 2.30 x 10(-27) Nm2 radian(-1)) to approximately 17 degrees (C = 0.13 x 10(-27) Nm2 radian(-1)) at 25 degrees C. We favor a mechanism in which cofilin binding shifts the equilibrium between thermal ErIA-actin filament conformers, and facilitates two distinct structural changes in actin. One is local in nature, which affects the structure of actin's C terminus and is likely to mediate nearest-neighbor cooperative binding and filament severing. The second is a change in the internal dynamics of actin, which displays non-nearest-neighbor cooperativity and increases the torsional flexibility of filaments. The long-range effects of cofilin on the torsional dynamics of actin may accelerate P(i) release from filaments and modulate interactions with other regulatory actin filament binding proteins.

Actin Cytoskeleton↗
PubMed2005

Rigidity and flexibility of dipeptidyl peptidase IV: crystal structures of and docking experiments with DPIV.

Dipeptidyl peptidase IV (DPIV) is an alpha,beta-hydrolase-like serine exopeptidase, which removes dipeptides, preferentially with a C-terminal l-Pro residue, from the N terminus of longer peptide substrates. Previously, we determined the tetrameric 1.8A crystal structure of native porcine DPIV. Each monomer is composed of a beta-propeller and a catalytic domain, which together embrace an internal cavity housing the active centre. This cavity is connected to the bulk solvent by a "propeller opening" and a "side opening". Here, we analyse DPIV complexes with a t-butyl-Gly-Pro-Ile tripeptide, Pro-boroPro, a piperazine purine compound, and aminoethyl phenyl sulfonylfluoride. The latter two compounds bind to the active-site groove in a compact and a quite bulky manner, respectively, causing considerable shifts of the catalytic Ser630 side-chain and of the Tyr547 phenolic group, which forms the oxyanion hole. The tripeptide, mimicking a peptide substrate, is clamped to the active site through tight interactions via its N-terminal alpha-ammonium group, the P2 carbonyl group, the P1-l-Pro side-chain, the C-terminal carboxylate group, and the stable orthoacid ester amide formed between the scissile peptide carbonyl group and Ser630 O(gamma). This stable trapping of the tripeptide could be due to stabilization of the protonated His740 imidazolium cation by the adjacent negatively charged C-terminal carboxylate group, preventing proton transfer to the leaving group nitrogen atom. Docking experiments with the compact rigid 58 residue protein aprotinin, which had been shown to be processed by DPIV, indicate that the Arg1-Pro2 N terminus can access the DPIV active site only upon widening of its side openings, probably by separation of the first and the last propeller blades, and/or of the catalytic and the propeller domain.

Animals↗
PubMed2006

Elucidating quantitative stability/flexibility relationships within thioredoxin and its fragments using a distance constraint model.

Numerous quantitative stability/flexibility relationships, within Escherichia coli thioredoxin (Trx) and its fragments are determined using a minimal distance constraint model (DCM). A one-dimensional free energy landscape as a function of global flexibility reveals Trx to fold in a low-barrier two-state process, with a voluminous transition state. Near the folding transition temperature, the native free energy basin is markedly skewed to allow partial unfolded forms. Under native conditions the skewed shape is lost, and the protein forms a compact structure with some flexibility. Predictions on ten Trx fragments are generally consistent with experimental observations that they are disordered, and that complementary fragments reconstitute. A hierarchical unfolding pathway is uncovered using an exhaustive computational procedure of breaking interfacial cross-linking hydrogen bonds that span over a series of fragment dissociations. The unfolding pathway leads to a stable core structure (residues 22-90), predicted to act as a kinetic trap. Direct connection between degree of rigidity within molecular structure and non-additivity of free energy is demonstrated using a thermodynamic cycle involving fragments and their hierarchical unfolding pathway. Additionally, the model provides insight about molecular cooperativity within Trx in its native state, and about intermediate states populating the folding/unfolding pathways. Native state cooperativity correlation plots highlight several flexibly correlated regions, giving insight into the catalytic mechanism that facilitates access to the active site disulfide bond. Residual native cooperativity correlations are present in the core substructure, suggesting that Trx can function when it is partly unfolded. This natively disordered kinetic trap, interpreted as a molten globule, has a wide temperature range of metastability, and it is identified as the "slow intermediate state" observed in kinetic experiments. These computational results are found to be in overall agreement with a large array of experimental data.

Computer Simulation↗
PubMed2006

Translocation of a tRNA with an extended anticodon through the ribosome.

Coordinated translocation of the tRNA-mRNA complex by the ribosome occurs in a precise, stepwise movement corresponding to a distance of three nucleotides along the mRNA. Frameshift suppressor tRNAs generally contain an extra nucleotide in the anticodon loop and they subvert the normal mechanisms used by the ribosome for frame maintenance. The mechanism by which suppressor tRNAs traverse the ribosome during translocation is poorly understood. Here, we demonstrate translocation of a tRNA by four nucleotides from the A site to the P site, and from the P site to the E site. We show that translocation of a punctuated mRNA is possible with an extra, unpaired nucleotide between codons. Interestingly, the NMR structure of the four nucleotide anticodon stem-loop reveals a conformation different from the canonical tRNA structure. Flexibility within the loop may allow conformational adjustment upon A site binding and for interacting with the four nucleotide codon in order to shift the mRNA reading frame.

Anticodon↗
PubMed2006

Two parts of the T3S4 domain of the hook-length control protein FliK are essential for the substrate specificity switching of the flagellar type III export apparatus.

The switch in export specificity of the type III flagellar protein export apparatus from rod/hook type to filament type is believed to occur upon completion of hook assembly by way of an interaction of the type III secretion substrate specificity switch (T3S4) domain of the hook-length control protein FliK, with the integral membrane export apparatus component FlhB. The T3S4 domain of FliK (FliKT3S4) consisting of amino acid residues 265-405 has an unstable and flexible conformation in its last 35 residues (FliKCT). To investigate the role of FliKT3S4 in substrate specificity switching, we studied the effect of deletions and point mutations within this domain and characterized suppressor mutations. Deletions of ten amino acid residues within the region of residues 301-350 and five amino acids of residues 401-405 abolished switching of export specificity. Site directed mutagenesis showed that highly conserved residues, Val302, Ile304, Leu335, Val401 and Ala405, are essential, and that the five C terminal residues (401-405) are restricted in conformation for the switching process. Suppressor mutant analysis of the fliK(S319Y) mutant, which produces extended hooks with filaments attached due to delayed switching, suggested that FliKT3S4 interacts with the C terminal half of the cytoplasmic domain of FlhB (FlhBC). We propose a two step binding model of FliKT3S4 and FlhBC, in which residues 301-350 of FliK bind to FlhBC upon hook assembly completion at about 55 nm, and then unfolded FliKCT binds to FlhBC to trigger the switch in substrate specificity.

Amino Acid Sequence↗
PubMed2006

The 15 SCR flexible extracellular domains of human complement receptor type 2 can mediate multiple ligand and antigen interactions.

Complement receptor type 2 (CR2, CD21) is a cell surface protein that links the innate and adaptive immune response during the activation of B cells. The extracellular portion of CR2 comprises 15 or 16 short complement regulator (SCR) domains, for which the overall arrangement in solution is unknown. This was determined by constrained scattering and ultracentrifugation modelling. The radius of gyration of CR2 SCR 1-15 was determined to be 11.5 nm by both X-ray and neutron scattering, and that of its cross-section was 1.8 nm. The distance distribution function P(r) showed that the overall length of CR2 SCR 1-15 was 38 nm. Sedimentation equilibrium curve fits gave a mean molecular weight of 135,000 (+/- 13,000) Da, in agreement with a fully glycosylated structure. Velocity experiments using the g*(s) derivative method gave a sedimentation coefficient of 4.2 (+/- 0.1) S. In order to construct a model of CR2 SCR 1-15 for constrained fitting, homology models for the 15 SCR domains were combined with randomised linker peptides generated by molecular dynamics simulations. Using an automated procedure, the analysis of 15,000 possible CR2 SCR 1-15 models showed that only those models in which the 15 SCR domains were flexible but partially folded back accounted for the scattering and sedimentation data. The best-fit CR2 models provided a visual explanation for the versatile interaction of CR2 with four ligands C3d, CD23, gp350 and IFN-alpha. The flexible location of CR2 SCR 1-2 is likely to facilitate interactions of C3d-antigen complexes with the B cell receptor.

Animals↗
PubMed2005

Barnase thermal titration via molecular dynamics simulations: detection of early denaturation sites.

The thermal stability of barnase has been studied using constant pressure and temperature (CPT) molecular dynamics at different temperatures. Barnase X-ray coordinates were obtained from the Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank (PDB code:1rnb). Simulations were performed at 285, 295, 300, 335, 345, and 395 K in explicit water under periodic boundary conditions for 280 ps. For each simulation, conformations were saved every 0.2 ps. Root mean square deviation (RMSD) values were calculated relative to the starting structure at 300 K and at time t = 0. Root mean square fluctuation (RMSF) values were calculated relative to the average structure obtained from the 300K simulation. Both root mean square deviation and fluctuation analysis indicated the presence of discrete regions of hyper-sensitivity along the barnase polypeptide chain. These regions exhibited spikes in flexibility prior to any global structural changes. The specific changes in barnase backbone flexibility are accompanied by increased phi/psi angle fluctuations. These results suggest the presence of early denaturation sites or denaturation nuclei whose local structure is disrupted prior to global structure disruption. Identification of denaturation nuclei suggests that appropriate amino acid replacements at these sites may lead to the design and development of more stable barnase mutants. This strategy of identifying denaturation nuclei in protein structures may represent a first step in the design of more stable protein structures.

Amino Acid Sequence↗
PubMed2006

Structural and dynamical properties of different protonated states of mutant HIV-1 protease complexed with the saquinavir inhibitor studied by molecular dynamics simulations.

To understand the basis of drug resistance, particularly of the HIV-1 PR, three molecular dynamics (MD) simulations of HIV-1 PR mutant species, G48V, complexed with saquinavir (SQV) in explicit aqueous solution with three protonation states, diprotonation on Asp25 and Asp25' (Di-pro) and monoprotonation on each Asp residue (Mono-25 and Mono-25'). For all three states, H-bonds between saquinavir and HIV-1 PR were formed only in the two regions, flap and active site. It was found that conformation of P2 subsite of SQV in the Mono-25 state differs substantially from the other two states. The rotation about 177 degrees from the optimal structure of the wild type was observed, the hydrogen bond between P2 and the flap residue (Val48) was broken and indirect hydrogen bonds with the three residues (Asp29, Gly27, and Asp30) were found instead. In terms of complexation energies, interaction energy of -37.3 kcal/mol for the Mono-25 state is significantly lower than those of -30.7 and -10.7kcal/mol for the Mono-25' and Di-pro states, respectively. It was found also that protonation at the Asp25 leads to a better arrangement in the catalytic dyad, i.e., the Asp25-Asp25' interaction energy of -8.8 kcal/mol of the Mono-25 is significantly lower than that of -2.6kcal/mol for the Mono-25' state. The above data suggest us to conclude that interaction in the catalytic area should be used as criteria to enhance capability in drug designing and drug screening instead of using the total inhibitor/enzyme interaction.

Binding Sites↗
PubMed2006

Modelling NifH2 protein of Clostridium pasteurianum reveals clues about its physiological function.

Clostridium pasteurianum is an anaerobic free-living nitrogen fixer. As a unique feature, the organism contains five extra nifH-like genes in addition to nifH1. Detailed analysis with respect to the structure and function of the nifH-like gene products is missing due to the lack of information about the presence of their translation products in the cell. Recent work indicates that the nifH2 gene is transcribed and translated into a polypeptide of expected size in nitrogen-fixing cells of C. pasteurianum and is regulated both at the transcriptional and translational levels. However, the current data do not reveal the physiological function of the NifH2 protein. In this study, we have used computer tools and the NifH1 of C. pasteurianum as the template to predict a possible tertiary structure and assign a putative function for NifH2 protein. A comparison of the structures of the NifH1 and modelled NifH2 revealed similarities in the polypeptide conformations for both monomers. Analysis of the properties of nucleotide binding, dimer interacting and cluster containing regions did not reveal major differences between NifH1 and modelled NifH2, although minor differences were observed. Rigid docking results revealed the possibility of formation of a NifH1-NifH2 heterodimer as well as formation of a NifH2 homodimer. We, therefore, propose that NifH2 can form a dimer with NifH1, albeit less efficiently and may function as a regulatory Fe-protein.

Amino Acid Sequence↗
PubMed2005

Measurement of lumbar spine loads and motions during rotational mobilization.

OBJECTIVES: To measure the loads acting at the lumbar spine and the resulting motions during rotational mobilization. METHODS: Twenty healthy subjects were subjected to right rotational mobilization of different grades. The magnitude and frequency of mobilization loads were decided by an experienced manipulative therapist to be appropriate for each mobilization grade. Subjects were positioned on a specially constructed plinth capable of measuring forces and moments about 3 axes. The 3-dimensional movements of the lumbar spine were captured by an electromagnetic tracking device. RESULTS: In the starting positions, the lumbar spines were found to be flexed, axially rotated to the right, and laterally bent to the left. As the mobilization grade increased, the spine was axially rotated further into the range. Rotational mobilization was found to induce oscillatory moments and movements of the spine in all 3 anatomical planes. The twisting moment and movement were generally accompanied by lateral bending moment and movement in the opposite direction. The mean amplitudes of the moment and movement oscillations were small and found to be largest for grade III mobilization. CONCLUSION: The mechanical effects of rotational mobilization are not restricted to axial rotation of the spine as the name may have suggested. Rotational mobilization may be able to restore lost movements of the lumbar spine in any of the 3 planes. The method developed in this study showed good reliability and may be considered to assess treatment outcome and changes in spinal stiffness after therapy.

Adult↗
PubMed2005

The biomechanical and clinical significance of the lumbar erector spinae flexion-relaxation phenomenon: a review of literature.

OBJECTIVES: The aim of this study was to review the biomedical literature to ascertain the biomechanical and clinical significance of the lumbar erector spinae flexion-relaxation phenomenon (FRP). DATA SOURCES: Index Medicus via PubMed, the Noble Science Library's e-journal archives, and the Manual Alternative and Natural Therapy Index System databases were searched using the same search terms. DISCUSSION: The presence of the FRP during trunk flexion represents myoelectric silence consistent with increased load sharing of the posterior discoligamentous passive structures. Passive contributions from erector spinae stretching during the flexion posture and active contributions from other muscles (quadratus lumborum and deep erector spinae among others) further assist in load sharing in the trunk flexion posture. A number of studies have shown differences in the FRP between patients with chronic low back pain and healthy individuals, and the reliability of the assessment. Persistent activation of the lumbar erector spinae musculature among patients with back pain may represent the body's attempt to stabilize injured or diseased spinal structures via reflexogenic ligamentomuscular activation thereby protecting them from further injury and avoiding pain. CONCLUSIONS: The myoelectric silencing of the erector spinae muscles in the trunk flexion posture is indicative of increased load sharing on passive structures, which tissues have been found to fail under excessive loading conditions and shown to be a source of low back pain. The studies that show differences in the presence of the FRP among patients and control subjects are encouraging for this type of clinical assessment and suggest that assessment of the FRP is a valuable objective clinical tool to aid in the diagnosis and treatment of patients with low back pain.

Biomechanical Phenomena↗
PubMed2005

Validity of the lateral gliding test as tool for the diagnosis of intervertebral joint dysfunction in the lower cervical spine.

OBJECTIVE: To determine if the lateral gliding test for the cervical spine is a valid clinical test compared with radiological assessment as a tool for the diagnosis of intervertebral joint dysfunctions in the lower cervical spine in patients presenting with mechanical neck pain. METHODS: Twenty-five patients with mechanical neck pain presenting with an asymmetry of at least 5 degrees between left and right cervical lateral flexion and diagnosed with an intervertebral joint dysfunction in the lower cervical spine based on the lateral gliding test were studied. Two anterior-posterior x-rays were performed on each patient at maximum end-range of right and left cervical lateral flexion. The intervertebral motion was compared between the hypomobile side and the contralateral side at the level diagnosed as hypomobile by the lateral gliding test. RESULTS: The asymmetry between left and right cervical lateral flexion motion was 7.64 degrees +/- 2.25 degrees (P = .001). Fourteen patients were diagnosed with intervertebral dysfunctions on the right side, whereas 11 patients showed cervical hypomobility on the left. Joint dysfunction at the C3 vertebra was the most prevalent (n = 16), followed by the dysfunction at the C4 vertebra (n = 9). The intervertebral radiological motion at the hypomobile side (mean 19.1, SD 2.1 mm) was 3.44 +/- 1.9 mm less than the intervertebral radiological motion at the contralateral side (mean 22.6, SD 2.5 mm) with P = .002. CONCLUSIONS: The lateral gliding test for the cervical spine was as good as a radiological assessment for the diagnosis of intervertebral dysfunctions in the lower cervical spine.

Adult↗
PubMedDate not supplied

The effects of active release technique on hamstring flexibility: a pilot study.

OBJECTIVE: The aim of this study is to determine if active release technique (ART) significantly increases hamstring flexibility in healthy male participants. METHODS: Twenty physically active male participants with no current or previous history of lower extremity injury received ART on the origins and insertions of the hamstrings and dorsal sacral ligament. The sit-and-reach test was used before and after treatment to determine hamstring flexibility. Summary statistics were calculated, and pre and post hamstring flexibility scores were compared using a related samples t test. RESULTS: There was a significant difference between the pre- and posttest groups (mean pre = 35.5 cm, df = 19, SD = 7.56; mean post = 48.3 cm, df = 19, SD = 7.07; P = .0015). All 20 participants increased their sit-and-reach scores following the application of ART. CONCLUSIONS: This study demonstrated that a single ART treatment increased hamstring flexibility in a group of healthy, active male participants.

Adult↗
PubMedDate not supplied

Comparative study of hands-on therapy with active exercises vs education with active exercises for the management of upper back pain.

OBJECTIVE: The aim of this study was to compare hands-on therapy, including heat, massage, and active exercises with postural education that emphasized increased self-efficacy and postural self-awareness along with education about the physiology of the disorder, and prescribed daily active exercises. SUBJECTS: Twenty-four randomly selected women, 12 custodians and 12 students, with neck and shoulder pain and stiffness. METHODS: All subjects received a medical examination and x-ray before the study to rule out any pre-existing neurologic deficits and an evaluation that included history taking and self-reporting of pain according to a numeric pain scale. Student participants received education and exercise instructions to be continued daily. The custodial workers received once-per-week hands-on treatment. RESULTS: Data were compared using a nonparametric analysis (Wilcoxon signed rank test) and showed evidence of statistically significant reductions in neck, shoulder, and back stiffness and shoulder muscle tension for most of the study subjects. CONCLUSION: Treatment of repetitive stress injuries that combines maintenance of daily active exercises prescribed and modeled by a professional therapist, which emphasize postural awareness to correct poor posture and provide a basic physiological understanding of the disorder, is as crucial to reducing upper back and neck pain and stiffness as hands-on therapy with active exercise provided in a clinical setting.

Adult↗
PubMed2006

Coupling behavior of the cervical spine: a systematic review of the literature.

OBJECTIVE: The purpose of this study was to investigate evidence of consistency of reported directional coupling patterns among selected studies and to determine its use in manual medical treatment. METHODS: The study was a systematic literature review of English-only journals using PubMed and CINAHL. The keywords included "cervical vertebrae," "biomechanics," "coupling," and "three-dimensional movement" and required coupling directional assessment of individual spine segments. RESULTS: Four 2-dimensional and 8 3-dimensional studies met inclusion criteria. This study found 100% agreement in coupling direction (side flexion and rotation to the same side) in lower cervical vertebral segments (C2-3 and lower) and variation in coupling patterns in the upper cervical segments of occiput-C1 (during side flexion initiation) and C1-2. Dissimilarities may be explained by differences in measurement devices, movement initiation, in vivo vs in vitro specimens, and anatomical variations. CONCLUSIONS: These findings suggest that use of 3-dimensional analyzed cervical coupling patterns for the lower cervical vertebral during apposition and treatment application may show clinical use for manual clinicians. The use of directional coupling based on 2-dimensional cervical coupling patterns or upper cervical spine coupling that addresses C1-2 should be questioned.

Biomechanical Phenomena↗
PubMed2006

Comparative study of torsional and bending properties for six models of nickel-titanium root canal instruments with different cross-sections.

This study investigated the influence of cross-section profile on the mechanical behaviors of six commercial nickel-titanium (NiTi) root canal instruments using the finite element method. The nonlinear mechanical characteristics of the NiTi alloy were taken into account. The six root canal instruments studied were ProTaper, Hero642, Mtwo, ProFile, Quantec, and NiTiflex. Mathematical models for these instruments were constructed and their performances were analyzed under equal torque conditions. The ProTaper and Hero642 models achieved the lowest stress levels that made them the most torque-resistant while the NiTiflex model was the poorest. The maximum stress value and the stress distribution in a model were found strongly influenced by the cross-section profile. Factors affecting the stress distribution include the cross-sectional inertia, depth of the flute, area of the inner core, radial land, and peripheral surface ground. As the area of the inner core of the cross-section increased, the model was more torque-resistant.

Dental Alloys↗
PubMed2006

Effect of setting conditions on mineral trioxide aggregate flexural strength.

This study evaluated the effect of setting conditions (time and hydration) on mineral trioxide aggregate (MTA) flexural strength. MTA beam specimens were allowed to set for either 24 or 72 hours with specimens exposed to moisture on either one or two specimen surfaces. These moisture conditions were used to simulate MTA setting with only external tissue moisture (one-sided moisture) versus tissue moisture in combination with a moistened intracanal cotton pellet (two-sided moisture). Ten specimens were stored at 37 degrees C under each of the four experimental setting conditions (1) 24-hour/moist/2-sided; (2) 24-hour/moist/1-sided; (3) 72-hour/moist/2-sided; (4) 72-hour/moist/1-sided. After storage at respective setting conditions, MTA specimens were tested to failure with three-point bend test to measure flexural strength. Flexural strength of the 24h/moist/2-sided specimens, 14.27 +/- 1.96 MPa, was significantly higher (p < or = 0.05) than the flexural strength values associated with conditions two, three, and four, respectively, 10.77 +/- 1.44, 11.16 +/- 0.96, 11.18 +/- 0.99 MPa, which were not significantly different from each other (p > 0.05). Clinically, these results suggest that a moistened cotton pellet should be placed on the intracanal MTA surface under a temporary restoration; and if possible, to optimize flexural strength, the moistened pellet should only remain in place for 24 hours.

Aluminum Compounds↗
PubMed2006

Comparison of defects in ProFile and ProTaper systems after clinical use.

The purpose of this study was to compare the incidence and mode of instrument separation of the two nickel-titanium (NiTi) rotary systems that were used according to a predefined schedule of clinical use by the same group of operators. A total of 166 ProFile and 325 ProTaper instruments, discarded from this endodontic clinic over 17 months, was analyzed. The incidences of instrument separation were 7% for ProFile and 14% for ProTaper (p < 0.05). The proportion of unwinding defects was 5% in ProFile and 0.3% in ProTaper instruments (p < 0.01). Flexural fatigue was implicated in the majority of separations in both groups. The results of this study indicated that while ProTaper was more likely to separate without warning, ProFile tended to exhibit unwinding of flutes more frequently.

Dental Alloys↗