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J Higo

Publications and source records attributed to J Higo.

18 recordsLinked to original sources
PubMed2001

Large vortex-like structure of dipole field in computer models of liquid water and dipole-bridge between biomolecules.

We propose a framework to describe the cooperative orientational motions of water molecules in liquid water and around solute molecules in water solutions. From molecular dynamics (MD) simulation a new quantity "site-dipole field" is defined as the averaged orientation of water molecules that pass through each spatial position. In the site-dipole field of bulk water we found large vortex-like structures of more than 10 A in size. Such coherent patterns persist more than 300 ps although the orientational memory of individual molecules is quickly lost. A 1-ns MD simulation of systems consisting of two amino acids shows that the fluctuations of site-dipole field of solvent are pinned around the amino acids, resulting in a stable dipole-bridge between side-chains of amino acids. The dipole-bridge is significantly formed even for the side-chain separation of 14 A, which corresponds to five layers of water. The way that dipole-bridge forms sensitively depends on the side-chain orientations and thereby explains the specificity in the solvent-mediated interactions between biomolecules.

Amino Acids↗
PubMed2001

Energy landscape of a peptide consisting of alpha-helix, 3(10)-helix, beta-turn, beta-hairpin, and other disordered conformations.

The energy landscape of a peptide [Ace-Lys-Gln-Cys-Arg-Glu-Arg-Ala-Nme] in explicit water was studied with a multicanonical molecular dynamics simulation, and the AMBER parm96 force field was used for the energy calculation. The peptide was taken from the recognition helix of the DNA-binding protein, c-MYB: A rugged energy landscape was obtained, in which the random-coil conformations were dominant at room temperature. The CD spectra of the synthesized peptide revealed that it is in the random state at room temperature. However, the 300 K canonical ensemble, Q(300K), contained alpha-helix, 3(10)-helix, beta-turn, and beta-hairpin structures with small but notable probabilities of existence. The complete alpha-helix, imperfect alpha-helix, and random-coil conformations were separated from one another in the conformational space. This means that the peptide must overcome energy barriers to form the alpha-helix. The overcoming process may correspond to the hydrogen-bond rearrangements from peptide-water to peptide-peptide interactions. The beta-turn, imperfect 3(10)-helix, and beta-hairpin structures, among which there are no energy barriers at 300 K, were embedded in the ensemble of the random-coil conformations. Two types of beta-hairpin with different beta-turn regions were observed in Q(300K). The two beta-hairpin structures may have different mechanisms for the beta-hairpin formation. The current study proposes a scheme that the random state of this peptide consists of both ordered and disordered conformations. In contrast, the energy landscape obtained from the parm94 force field was funnel like, in which the peptide formed the helical conformation at room temperature and random coil at high temperature.

Circular Dichroism↗
PubMed2000

Homology modeling of human leptin/leptin receptor complex.

Leptin receptor mediates the weight regulatory signal carried by the adipocyte-secreted peptide hormone, leptin. It is important to understand the atomic interactions between leptin and the receptor for the therapeutic applications. However, the structure of leptin receptor has not yet been determined. Leptin shows structural similarity to G-CSF, while leptin receptor is similar in amino acid sequence to G-CSF receptor. Because of the similarity between leptin/leptin receptor complex and G-CSF/G-CSF receptor complex, we tried to build a model structure of leptin/leptin receptor complex with the crystal structure of the G-CSF/G-CSF receptor complex as the template. The obtained model for the complex was consistent with the results of the amino acid replacement and deletion experiments. The observation suggests that the model is useful to lead the experimental study on the interaction between leptin and the receptor.

Amino Acid Sequence↗
PubMed2000

Solvent density and long-range dipole field around a DNA-binding protein studied by molecular dynamics.

The distribution and orientation of solvent around a DNA-binding protein, 434 Cro, were investigated by molecular dynamics simulations with a periodic-boundary condition. The protein was treated in two states: charged and neutral. The computed high-density sites of the solvent around the protein correlated well with the experimentally determined crystal-water sites, in both the charged and neutral states. A local density map, introduced to investigate the solvent density around the highly mobile regions of the protein, showed a hydration shell around hydrophobic sidechains and hydrogen-bondable sites around hydrophilic sidechains, and also showed that the solvent density is sensitive to the slight concaves of the sidechain surface. The long-range solvent-dipole field was observed around the protein, where the pattern of the dipole ordering was considerably different between the charged and neutral states. A local solvent-dipole field was introduced, and the pattern of the dipole ordering was different between the hydrophobic and hydrophilic sidechains. The dipole field from the charged state provided a higher correlation to the electrostatic field obtained from the Poisson-Boltzmann's equation than that from the neutral state, although the correlation become weak quickly for the both states with increasing the protein-solvent distance.

DNA-Binding Proteins↗
PubMed2000

Free energy landscapes of peptides by enhanced conformational sampling.

The free energy landscapes of peptide conformations in water have been observed by the enhanced conformational sampling method, applying the selectively enhanced multicanonical molecular dynamics simulations. The conformations of the peptide dimers, -Gly-Gly-, -Gly-Ala-, -Gly-Ser-, -Ala-Gly-, -Asn-Gly-, -Pro-Gly-, -Pro-Ala-, and -Ala-Ala-, which were all blocked with N-terminal acetyl and C-terminal N-methyl groups, were individually sampled with the explicit TIP3P water molecules. From each simulation trajectory, we obtained the canonical ensemble at 300 K, from which the individual three-dimensional landscape was drawn by the potential of mean force using the three reaction coordinates: the backbone dihedral angle, psi, of the first amino acid, the backbone dihedral angle, phi, of the second amino acid, and the distance between the carbonyl oxygen of the N-terminal acetyl group and the C-terminal amide proton. The most stable state and several meta-stable states correspond to extended conformations and typical beta-turn conformations, and their free energy values were accounted for from the potentials of mean force at the states. In addition, the contributions from the intra-molecular energies of peptides and those from the hydration effects were analyzed. Consequently, the stable beta-turn conformations in the free energy landscape were consistent with the empirically preferred beta-turn types for each amino acid sequence. The thermodynamic values for the hydration effect were decomposed and they correlated well with the empirical values estimated from the solvent accessible surface area of each molecular conformation during the trajectories. The origin of the architecture of protein local fragments was analyzed from the viewpoint of the free energy and its decomposed factors.

Algorithms↗
PubMed1999

Enhanced conformational diversity search of CDR-H3 in antibodies: role of the first CDR-H3 residue.

Through a conformation search by a simulation calculation, the relationships between the amino acid sequences and the conformations of the third complementarity-determining region of the antibody heavy chain (CDR-H3) were investigated to characterize the large conformational varieties of antibodies. Here, we focused on the structural role of the first CDR-H3 residue, and we selected two antibodies, 28B4 and PLG, whose CDR-H3 conformations are significantly different, having Trp and Gly at the first position, respectively. Multicanonical molecular dynamics simulations, with the advantage of enhanced sampling efficiency, were performed for the CDR-H3 fragments of 28B4 and PLG, and a modified CDR-H3 model of 28B4, where the first Trp residue was substituted with Gly. When the first CDR-H3 residue is Trp, almost all of the observed CDR-H3 loops were bent at the first residue. In contrast, when the first residue is Gly, large varieties of loop conformations were observed. The structural role of this Gly residue is discussed from the perspective of the other antibody structures in the database. When the surrounding residues were included in the calculations, CDR-H3 loop structures similar to those in the crystal structures were reproduced as the major conformations for both the 28B4 and PLG antibodies.

Algorithms↗
PubMed1998

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

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

Algorithms↗
PubMed1997

A theoretical approach to the bell-shaped dependency of cell proliferation on the hormone concentration.

Binding of human growth hormones (hGH) to the receptors was studied with a theoretical, molecular-level model. An hGH has two sites bindable to different receptors with different binding energies. In the model the hGHs diffusively moved in a box (i.e. the volume of solution), and receptors on the bottom face the box (i.e. a membrane). The system consisted of a number of hGHs and receptors, which could form hGH-[receptor]2 or hGH-receptor complexus. In a complex, small inter-molecular positional fluctuations were allowed with keeping the inter-molecular binding. Partition function of the system was calculated. In a low hGH-concentration range, free receptors were dominant on the membrane; in a medium concentration range, hGH-[receptor]2 complexus, which induce cell-proliferation, were dominant, and in a high concentration range, hGH-receptor complexus, which inhibit the proliferation, were dominant. This dependency (bell-shaped dependency) of formation of hGH-[receptor]2 complex on the hGH concentration agreed well with experimental observation. The values of EC50 (hGH concentration at that the cell-proliferation rate rose to 50% of the maximum rate by the formation of hGH-[receptor]2 complexus) and IC50 (hGH concentration at that the proliferation rate decreased to 50% of the maximum by the formation of hGH-receptor complexus) from my method were 18 pM and 2.2 microM, respectively. By calculating thermodynamic quantities (i.e. entropy and enthalpy), factors that determine the bell-shaped dependency were obtained. At the medium concentration, the entropy of free hGHs played an important role in stabilizing the hGh-[receptor]2 complex. Small changes in binding energies or in inter-molecular positional fluctuations largely changed the dependency of the complex formation on the hGH concentration. This method is useful in explaining the experimental results that small molecular modification largely changes the formation of the complex.

Cell Division↗
PubMed1997

Protein dynamics determined by backbone conformation and atom packing.

To study the factors determining the collective motions in thermal, conformational fluctuations of a globular protein, molecular dynamics simulations were performed with a backbone model and an atomic-level model. In the backbone model, only the C alpha atoms were explicitly treated with two types of pairwise interactions assigned between the C alpha atoms; atom-packing interactions to take into account the effect of tight atom packing in the protein interior and chain-restoring interactions to maintain the backbone around the native conformation. A quasi-harmonic method was used to decompose the overall fluctuations into independent, collective modes. The modes assigned to large conformational fluctuations showed a good correlation between the backbone and atomic-level models. From this study, it was suggested that the collective modes were motions in which a protein fluctuates, keeping the tertiary structure around the native one and avoiding backbone overlap and, hence, rough aspects of the collective modes can be derived without details of the atomic interactions. The backbone model is useful in obtaining the overall backbone motions of a protein without heavy simulations, even though the simulation starts from a poorly determined conformation of experiments and in sampling main chain conformations, from which the side chain conformations may be predicted.

Models, Chemical↗
PubMed1993

Modeling of protein loops by simulated annealing.

A method is presented to model loops of protein to be used in homology modeling of proteins. This method employs the ESAP program of Higo et al. (Higo, J., Collura, V., & Garnier, J., 1992, Biopolymers 32, 33-43) and is based on a fast Monte Carlo simulation and a simulated annealing algorithm. The method is tested on different loops or peptide segments from immunoglobulin, bovine pancreatic trypsin inhibitor, and bovine trypsin. The predicted structure is obtained from the ensemble average of the coordinates of the Monte Carlo simulation at 300 K, which exhibits the lowest internal energy. The starting conformation of the loop prior to modeling is chosen to be completely extended, and a closing harmonic potential is applied to N, CA, C, and O atoms of the terminal residues. A rigid geometry potential of Robson and Platt (1986, J. Mol. Biol. 188, 259-281) with a united atom representation is used. This we demonstrate to yield a loop structure with good hydrogen bonding and torsion angles in the allowed regions of the Ramachandran map. The average accuracy of the modeling evaluated on the eight modeled loops is 1 A root mean square deviation (rmsd) for the backbone atoms and 2.3 A rmsd for all heavy atoms.

Algorithms↗
PubMed1993

Conformational deformation in deoxymyoglobin by hydrostatic pressure.

Pressure effect on the equilibrium conformation in sperm whale deoxymyoglobin and its volume fluctuation are studied by the normal mode analysis and strain tensor analysis. The pressure-induced deformation of interhelix regions are found to be remarkably more compressed than the other parts of the molecule. The intrahelix compressibility is shown to be relatively small. We also calculate the compressibility of the three hydrophobic clusters, located at the bottom, distal, and proximal side of the heme. Its value is found to decrease in the indicated order. The average compressibility of these hydrophobic clusters is less than the average interhelix compressibility, even though there are large cavities in these clusters. In order to study overall deformation, we define a linear compressibility and calculate it for all pairs of C alpha atoms. The pressure-induced deformation is observed to be heterogeneous also in this analysis. The calculated root-mean-square displacement of the constituent atoms in the equilibrium conformation at 1,000 atm from those at 0 atm is 0.12 A, which is much smaller in magnitude than the average value of the atomic fluctuations at room temperature. In the water solvent, the volume excluded by the protein molecule in the equilibrium conformation is reduced by 0.9%, when the pressure is raised from 0 to 1,000 atm. The calculated magnitude of the root-mean-square volume fluctuation is 0.3% of the excluded volume at room temperature. The square of the volume fluctuation is given as a sum of contributions from individual normal modes. Contributions from low frequency normal modes are found to dominate over those from higher frequency normal modes. The estimated value of the isothermal compressibility of deoxymyoglobin is 9.37 x 10(-12) cm2/dyn.

Animals↗
PubMed1992

Development of an extended simulated annealing method: application to the modeling of complementary determining regions of immunoglobulins.

An extended simulated annealing process (ESAP) has been developed in order to obtain an ensemble of conformations of a peptide segment from a protein fluctuating at a given temperature. The annealing process was performed with a fast Monte Carlo method using the scaled collective variables developed by Noguti and Go. The system was divided into two parts: one consists of one or more peptide segments and is flexible around the main-chain and side-chain torsional angles; the other represents the rest of the molecule and was maintained fixed at the atomic positions determined by x-ray experiments. The target function included the nonbonding atomic interactions and a distance function to anchor the N and C terminal ends of each segment to the fixed part. Three systems of complementary determining regions (CDR) of antibodies were tested and compared to x-ray data: L2 loop (7 residues) of the light chain of lambda-type Bence-Jones protein, H1 and the H2 loops (14 residues) of McPC603, and H1 and H2 loops (12 residues) of HyHEL-5. Each state of CDR conformations was characterized at room temperature by the average of their coordinates (average conformation) and the internal energy. With a limited number of annealing processes (10), starting from the extended conformation, we have obtained states with conformations close to the observed x-ray structures, from 1.1 to 1.7 A root mean square deviation (rmsd) of main-chain atoms depending on the system. These states were identical or within 0.25 A rmsd of those of lowest internal energy. For unknown CDR structures the criteria of lowest internal energies from ESAP can be used to predict hypervariable loop structures in antibodies with an accuracy comparable to other methods.

Amino Acid Sequence↗