Hiromi Ishimura

Specific interactions between vitamin-D receptor and its ligands: Ab initio molecular orbital calculations in water

Vitamin D is recognized to play important roles not only in the bone metabolism and the regulation of Ca amount in the blood but also in the onset of immunological diseases. These physiological actions caused by vitamin D are triggered by the specific interaction between vitamin D receptor (VDR) and vitamin D. In the present study, we investigated the interactions between VDR and vitamin D derivatives using ab initio molecular simulation, in order to elucidate the reason for the significant difference in their effects on VDR activity. Based on the results simulated, we elucidated which parts of the derivatives and which residues of VDR mainly contribute to the specific binding between VDR and the derivatives at an electronic level. This finding will be helpful for proposing new vitamin D derivatives as a potent modulator or inhibitor against VDR.

Specific interactions between zinc metalloproteinase and its inhibitors: Ab initio fragment molecular orbital calculations

Bacteria secrete the enzyme pseudolysin (PLN) to degrade exocellular proteins, and the produced peptides are used as a nutrient for the bacteria. It is thus expected that inhibition of PLN can suppress bacterial growth. Since such inhibitors do not attack to bacteria directly, the risk of producing drug-resistance bacteria is less. However, endogenous proteinases such as the matrix metalloproteinases (MMPs) have active site similar to that of PLN, and there is a possibility that PLN inhibitors also inhibit the activity of MMPs, resulting in a loss of substrate degradation by these proteinases. Therefore, agents that inhibit the activity of only PLN and not MMPs are required. In the present study, we select two compounds (ARP101 and LM2) and investigate their specific interactions with PLN and MMPs by use of ab initio molecular simulations. Based on the results, we propose several novel compounds as candidates for potent PLN inhibition and investigate their binding properties with PLN, elucidating that the compound, in which a toluene group is introduced into LM2, has larger binding energy with PLN compared with the pristine LM2. Therefore, this compound is suggested to be a potent PLN inhibitor.

Ab initio fragment molecular orbital calculations on the specific interactions between amyloid-β peptides in an in vivo amyloid-β fibril

The accumulation of amyloid-beta (Aβ) fibrils in a brain has been recognized to contribute to the onset of Alzheimers disease (AD). However, the relation between the structure of the aggregate and its toxicity to AD patients remains to be fully elucidated. A recent solid-state NMR analysis for the tissue obtained from the brains of AD patients revealed that the Aβ aggregates have only a single structure with three-fold symmetry. We here investigate the specific interactions between Aβ peptides in the aggregate, using ab initio fragment molecular orbital calculations, to explain why such a unique structure possesses significant stability. The results indicate that the interactions between the Aβ peptides of the stacked Aβ pair are stronger than those between the Aβ peptides of the trimer with three-fold symmetry. Furthermore, it is elucidated that the charged amino-acid residues of Aβ mainly contribute to the strong attractive interactions between the paired Aβ peptides.

Ab initio molecular simulations on specific interactions between amyloid-β peptide and new curcumin derivatives

Accumulation of amyloid-β (Aβ) peptides in a brain is closely related with the pathogenesis of Alzheimers disease. To suppress the production of Aβ peptides, many kinds of agents have been developed for inhibiting the cleavage of amyloid precursor protein (APP) by secretases. However, because the secretases also play important roles the production of vital proteins for the human body, inhibitors for the secretases may have side effects. In the present study, to propose new agents for protecting the cleavage site of APP from the attacking of the γ-secretase, we investigate the specific interactions between a short APP peptide and curcumin derivatives, using protein-ligand docking as well as ab initio molecular simulations. Our proposed derivatives (curcumin VI and IX) are found to have a large binding energy with APP, and they are expected to be a potent inhibitor to the production of Aβ peptides.

Specific interactions between androgen receptor and its ligand: ab initio molecular orbital calculations in water

The Androgen Receptor (AR) is a family of nuclear receptor proteins and a ligand-activated transcription factor. Since its abnormal activation can cause the progression of prostate cancer, numerous types of antagonists against AR have been developed as promising agents for treating prostate cancers. We here investigated the specific interactions between AR and several types of non-steroid agents at an electronic level, using ab initio molecular simulations based on molecular mechanics and ab initio fragment molecular orbital (FMO) methods From the results obtained by FMO, we proposed novel agents as potent ligands against AR and investigated the binding properties between AR and these agents to confirm that some of them can bind more strongly with AR than the existing non-steroid agents and can be strongly effective ligands against AR.

Molecular dynamics and ab initio molecular orbital calculations on conformational change of amyloid-ß monomers in an in vivo amyloid-ß nonamer

The accumulation of amyloid beta (Aβ) oligomers and fibrils in a brain is deeply involved as a major cause of the onset of Alzheimers disease (AD). Recently, solid state NMR analysis for the tissues obtained from AD patients brain has revealed that Aβ aggregates in the tissues have a single patient-specific structure with three-fold symmetry. However, the relationship between the structure of accumulated Aβs and its toxicity to AD patients has not been fully elucidated. This threefold symmetry structure is markedly different from those of the in vitro Aβ fibrillar models. To clarify why this structure has significant stability, we here investigate the change in conformation of each Aβ peptide in the aggregates, using classical molecular dynamics (MD) simulations in water. Additionally ab initio fragment molecular orbital calculations are carried out for several structures obtained by the MD simulations to elucidate the specific interactions between Aβ peptides in the aggregates. The results simulated demonstrate that the interactions between the Aβ peptides which form stock the Aβ pairs are stronger than those between the Aß peptides of trimers having three-fold symmetry in each layer. In addition, the charged amino-acid residues of Aß peptide are found to contribute mainly to the significant stability of the Aβ aggregate.

Molecular dynamics and ab initio FMO calculations on the effect of water molecules on the interactions between androgen receptor and its ligand and cofactor

To reveal the effect of water molecules on the specific interactions between androgen receptor (AR) and ligand as well as cofactor, we investigated dynamical properties of the complex by the classical molecular dynamics simulations in an explicit water box. Moreover, electronic properties of the complex with and without the water molecules were calculated by ab initio fragment molecular orbital method to find that some of the water molecules contribute significantly to the interactions between AR, ligand and cofactor.

Effect of cofactor-binding on the specific interactions between androgen receptor and its ligand: Ab initio molecular simulations

To elucidate the effect of cofactor YLO on the structure and electronic properties of the androgen receptor (AR) and its ligand (TES) complex, we investigate the change in structure for the AR+TES and the AR+TES+YLO complexes by molecular dynamics simulations in explicit waters. We moreover perform ab initio fragment molecular orbital calculations for the complexes, in order to reveal the change in the specific interactions between AR and TES induced by YLO.