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Biomedical subjects

Yuko Okamoto

Publications and source records attributed to Yuko Okamoto.

16 recordsLinked to original sources
PubMed2006

Mycobacterial sulfolipid shows a virulence by inhibiting cord factor induced granuloma formation and TNF-alpha release.

Virulence mechanism of infection with Mycobacterium tuberculosis is currently focused to be clarified in the context of cell surface lipid molecule. Comparing two mycobacterial glycolipids, we observed toxicity and prominent granulomatogenic activity of trehalose 6,6'-dimycolate (TDM) injection in mice, evident by delayed body weight gain and histological observations, whereas 2,3,6,6'-tetraacyl trehalose 2'-sulfate (SL) was non-toxic and non-granulomatogenic. Likewise, TDM but not SL caused temporarily, but marked increase of lung indices, indicative of massive granuloma formation. Interestingly, co-administration of TDM and SL prevented these symptoms distinctively and SL inhibited TDM-induced release of tumor necrosis factor alpha (TNF-alpha) in a dose-dependent manner. Histological findings and organ index changes also showed marked inhibition of TDM induced granuloma formation by co-administration of SL. Simultaneous injection of SL together with TDM was highly effective for this protection, as neither injection 1h before nor after TDM injection showed highly inhibitory. In parallel studies on a cellular level, TDM elicited strong TNF-alpha release from alveolar but not from peritoneal macrophages in vitro. This effect was blocked when alveolar macrophages were incubated in wells simultaneously coated with TDM and SL, indicating that SL suppresses TDM-induced TNF-alpha release from macrophages. Our results suggest a novel mechanism by which SL could contribute to virulence at early stage of mycobacterial infection or stimulation with the glycolipids by counteracting the immunopotentiating effect of TDM.

Animals↗
PubMed2006

Theoretical studies of transition states by the multioverlap molecular dynamics methods.

The multioverlap molecular dynamics method gives a flat probability distribution in the multidimensional dihedral-angle-distance space, where the dihedral-angle distance of a configuration with respect to a reference state gives a measure for structural similarity. Hence, this method realizes a random walk among specific configurations in the multidimensional dihedral-angle-distance space at a constant temperature and explores widely in the configurational space. We applied the multioverlap molecular dynamics method to a pentapeptide, Met-enkephalin, in gas phase as a test system. Comparing the results of this method with those of the conventional canonical and multicanonical algorithms, we demonstrate its effectiveness. Furthermore, from the detailed free-energy landscape obtained from the results of the multioverlap molecular dynamics simulation, we obtain the transition state between two specific reference configurations of Met-enkephalin. We also deduce the transition pathway between the two specific reference configurations.

Algorithms↗
PubMed2006

Multibaric-multithermal ensemble molecular dynamics simulations.

We present new generalized-ensemble molecular dynamics simulation algorithms, which we refer to as the multibaric-multithermal molecular dynamics. We describe three algorithms based on (1) the Nosé thermostat and the Andersen barostat, (2) the Nosé-Poincaré thermostat and the Andersen barostat, and (3) the Gaussian thermostat and the Andersen barostat. The multibaric-multithermal simulations perform random walks widely both in the potential-energy space and in the volume space. Therefore, one can calculate isobaric-isothermal ensemble averages in wide ranges of temperature and pressure from only one simulation run. We test the effectiveness of the multibaric-multithermal algorithm by applying it to a Lennard-Jones 12-6 potential system.

Journal Article↗
PubMed2005

Structures of a peptide fragment of beta2-microglobulin studied by replica-exchange molecular dynamics simulations - towards the understanding of the mechanism of amyloid formation.

We investigate in detail the structural properties of the monomeric peptide fragment that corresponds to residues 21-31 of beta(2)-microglobulin. As a first step towards the understanding of the mechanism of the amyloid formation, we have performed a replica-exchange molecular dynamics simulation of this peptide with explicit water molecules. We analyze various structural properties as functions of temperature. Although the corresponding part of the native protein is a fully extended beta-strand, our results show that beta-hairpin structures are formed with high frequency around 310 K. We conjecture that this beta-hairpin formation is closely related to the amyloid fibrillogenesis.

Amyloid↗
PubMed2005

Correlations between periodontitis and loss of mandibular bone in relation to systemic bone changes in postmenopausal Japanese women.

A new method of measuring mandibular alveolar bone mineral density (BMD) was applied to 40 postmenopausal Japanese women aged 50-69 years exhibiting minimal to mild periodontal diseases. Lumbar spine BMD was measured by dual X-ray absorptiometry (DXA) and calcaneus speed of sound (SOS) by quantitative ultrasound (QUS). There were age-related decreases of alveolar BMD, calcaneus SOS and vertebral BMD. There were significant correlations between two of the respective bone mass values. Correlations between clinical dental findings and bone mass data including alveolar BMD, SOS and lumbar spine BMD were investigated. Significant correlations were demonstrated between alveolar BMD and calcaneus SOS or vertebral BMD. Alveolar BMD showed significant correlation with clinical dental findings including periodontal pocket depth and mobility as well as calcaneus SOS and lumbar spine BMD. Using multivariate analysis combinations of univariate predictors, including deoxypyridinoline (DPD), significantly predicted attachment levels. The SOS value was useful combined with other predictors for predicting attachment level. It was concluded that the new method of evaluating alveolar BMD is useful to predict systemic bone mass and strength as well as dental clinical findings.

Absorptiometry, Photon↗
PubMed2005

Molecular mechanism for stabilizing a short helical peptide studied by generalized-ensemble simulations with explicit solvent.

We study the folding mechanism of an analog of the C-peptide of ribonuclease A in explicit water by a replica-exchange multicanonical molecular dynamics simulation based on all-atom models. The multicanonical weight factor was determined by the combined use of the multicanonical replica-exchange method and the replica-exchange multicanonical algorithm. Using statistically reliable data thus obtained, we have examined the free-energy landscape of the peptide system. The global-minimum free-energy state in the landscape at room temperature has an alpha-helix structure with a distortion near the N-terminus. The state also has a salt bridge between Glu(-)-2 and Arg(+)-10 and an aromatic-aromatic interaction between Phe-8 and His(+)-12, both of which have been observed in x-ray and other experimental measurements. Principal component analysis clearly shows the different roles of these side-chain interactions in the peptide folding. The side-chain interaction between Phe-8 and His(+)-12 greatly enhances the stability of helical structure toward the C-terminal end, whereas the salt bridge between Glu(-)-2 and Arg(+)-10 mainly works as a restraint to prevent the alpha-helix structure from extending to the N-terminus. The free-energy landscape of C-peptide reveals a funnel-like shape where all of these interactions consistently exist only in the global-minimum state. This is the major reason why the native structure of the short helical peptide shows significant stability at low temperatures.

Algorithms↗
PubMed2004

Monte Carlo simulations in generalized isobaric-isothermal ensembles.

We present three generalized isobaric-isothermal ensemble Monte Carlo algorithms, which we refer to as the multibaric-multithermal, multibaric-isothermal, and isobaric-multithermal algorithms. These Monte Carlo simulations perform random walks widely in volume space and/or in potential energy space. From only one simulation run, one can calculate isobaric-isothermal-ensemble averages in wide ranges of pressure and temperature. We demonstrate the effectiveness of these algorithms by applying them to the Lennard-Jones 12-6 potential system with 500 particles.

Journal Article↗
PubMed2004

Replica-exchange extensions of simulated tempering method.

In this paper we consider combinations of two well-known generalized-ensemble algorithms, namely, simulated tempering and replica-exchange method. We discuss two examples of such combinations. One is the replica-exchange simulated tempering and the other is the simulated tempering replica-exchange method. In the former method, a short replica-exchange simulation is first performed and the simulated tempering weight factor is obtained by the multiple-histogram reweighting techniques. This process of simulated tempering weight factor determination is faster and simpler than that in the usual iterative process. A long simulated tempering production run is then performed with this weight factor. The latter method is a further extension of the former in which a simulated tempering replica-exchange simulation is performed with a small number of replicas. These algorithms are particularly useful for studying frustrated systems with rough energy landscape. We give the formulations of these two methods in detail and demonstrate their effectiveness taking the example of the system of a 17-residue helical peptide.

Journal Article↗
PubMed2004

Prediction of membrane protein structures by replica-exchange Monte Carlo simulations: case of two helices.

We test our prediction method of membrane protein structures with glycophorin A transmembrane dimer and analyze the predicted structures in detail. Our method consists of two parts. In the first part, we obtain the amino-acid sequences of the transmembrane helix regions from one of existing WWW servers and use them as an input for the second part of our method. In the second part, we perform a replica-exchange Monte Carlo simulation of these transmembrane helices with some constraints that indirectly represent surrounding lipid and water effects and identify the predicted structure as the global-minimum-energy state. The structure obtained in the case for the dielectric constant epsilon=1.0 is very close to that from the nuclear magnetic resonance experiments, while that for epsilon=4.0 is more packed than the native one. Our results imply that the helix-helix interaction is the main driving force for the native structure formation and that the stability of the native structure is determined by the balance of the electrostatic term, van der Waals term, and torsion term, and the contribution of electrostatic energy is indeed important for correct predictions. The inclusion of atomistic details of side chains is essential for estimating this balance accurately because helices are tightly packed.

Journal Article↗
PubMed2004

New approach to the first-order phase transition of Lennard-Jones fluids.

The multicanonical Monte Carlo method is applied to a bulk Lennard-Jones fluid system to investigate the liquid-solid phase transition. We take the example of a system of 108 argon particles. The multicanonical weight factor we determined turned out to be reliable for the energy range between -7.0 and -4.0 kJ/mol, which corresponds to the temperature range between 60 and 250 K. The expectation values of the thermodynamic quantities obtained from the multicanonical production run by the reweighting techniques exhibit the characteristics of first-order phase transitions between liquid and solid states around 150 K. The present study reveals that the multicanonical algorithm is particularly suitable for analyzing the transition state of the first-order phase transition in detail.

Journal Article↗
PubMed2004

Generalized-ensemble algorithms: enhanced sampling techniques for Monte Carlo and molecular dynamics simulations.

In complex systems with many degrees of freedom such as spin glass and biomolecular systems, conventional simulations in canonical ensemble suffer from the quasi-ergodicity problem. A simulation in generalized ensemble performs a random walk in potential energy space and overcomes this difficulty. From only one simulation run, one can obtain canonical ensemble averages of physical quantities as functions of temperature by the single-histogram and/or multiple-histogram reweighting techniques. In this article we review the generalized ensemble algorithms. Three well-known methods, namely, multicanonical algorithm (MUCA), simulated tempering (ST), and replica-exchange method (REM), are described first. Both Monte Carlo (MC) and molecular dynamics (MD) versions of the algorithms are given. We then present five new generalized-ensemble algorithms which are extensions of the above methods.

Algorithms↗
PubMed2003

Multioverlap simulations for transitions between reference configurations.

We introduce a procedure to construct weight factors, which flatten the probability density of the overlap with respect to some predefined reference configuration. This allows one to overcome free-energy barriers in the overlap variable. Subsequently, we generalize the approach to deal with the overlaps with respect to two reference configurations so that transitions between them are induced. We illustrate our approach by simulations of the brain peptide Met-enkephalin with the ECEPP/2 (Empirical Conformational Energy Program for Peptides) energy function using the global-energy-minimum and the second lowest-energy states as reference configurations. The free energy is obtained as functions of the dihedral and the root-mean-square distances from these two configurations. The latter allows one to identify the transition state and to estimate its associated free-energy barrier.

Journal Article↗
PubMed2002

A pH-dependent variation in alpha-helix structure of the S-peptide of ribonuclease A studied by Monte Carlo simulated annealing.

Low-energy conformations of the S-peptide fragment (20 amino acid residues long) of ribonuclease A were studied by Monte Carlo simulated annealing. The obtained lowest-energy structures have alpha-helices with different size and location, depending distinctively on the ionizing states of acidic amino acid residues. The simulation started from completely random initial conformation and was performed without any bias toward a particular structure. The most conspicuous alpha-helices arose from the simulation when both Glu 9 and Asp 14 were assumed to be electrically neutral, whereas the resulting conformations became much less helical when Asp 14 rather than Glu 9 was allowed to have a negative charge. Together with experimental evidence that the alpha-helix in the S-peptide is most stable at pH 3.8, we consider the helix formation need the carboxyl group of Asp 14 to be electrically neutral in this weakly acidic condition. In contrast, a negative charge at Asp 14 appears to function in support of a view that this residue is crucial to helix termination owing to its possibility to form a salt bridge with His 12. These results indicate that the conformation of the S-peptide depends considerably on the ionizing state of Asp 14.

Amino Acid Sequence↗