Kanako Shimamura

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.

Change in specific interactions between lactose repressor protein and DNA induced by ligand binding: molecular dynamics and molecular orbital calculations

Lactose repressor protein (LacR) plays an essential role in controlling the transcription mechanism of genomic information from DNA to mRNA. It has been elucidated that a ligand binding to LacR regulates allosterically the specific interactions between LacR and operator DNA. However, the effect of the ligand binding on the specific interactions has not been clarified at an atomic level. In this study, we performed classical molecular dynamics (MD) and ab initio fragment molecular orbital simulations to elucidate the effect of ligand binding at atomic and electronic levels. The MD simulations for the solvated complexes with LacR-dimer, DNA and ligand demonstrate that the binding of an inducer IPTG to LacR-dimer significantly changes the structure of LacR-monomer to cause strong interactions between LacR-monomers, resulting in weakening the interactions between LacR-dimer and DNA. In contrast, the binding of an anti-inducer ONPF to LacR-dimer was found to enhance the interactions between LacR-dimer and DNA. These findings are consistent with the functions of IPTG and ONPF as an inducer and an anti-inducer, respectively. We therefore proposed a simplified model for the effect of the ligand binding on the specific interactions between LacR-dimer and DNA.

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.

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 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.

141 Effect of ligand-binding on specific interactions between DNA and regulatory protein: molecular simulations based on MD and ab initio fragment MO methods

abstracted by the OH radical. The solvation around the base pairs stabilizes the dehydrogenated structures significantly, resulting in the acceleration of the attacking reaction by OH radical to the base pairs in the water. In the present study, we searched for the transition states of the attacking reactions of H and OH radicals to the DNA base pairs in the water, using the DFT calculations. The results elucidate that H radical affects significantly G-C base pair to cause the tautomeric reaction into G*-C* form, while OH radical can cause tautomeric reaction in A-T base pair, as shown above. The details of the results simulated will be presented at the meeting.

Specific interactions between DNA and regulatory protein controlled by ligand-binding: Ab initio molecular simulation

The catabolite activator protein (CAP) is one of the regulatory proteins controlling the transcription mechanism of gene. Biochemical experiments elucidated that the complex of CAP with cyclic AMP (cAMP) is indispensable for controlling the mechanism, while previous molecular simulations for the monomer of CAP+cAMP complex revealed the specific interactions between CAP and cAMP. However, the effect of cAMP-binding to CAP on the specific interactions between CAP and DNA is not elucidated at atomic and electronic levels. We here considered the ternary complex of CAP, cAMP and DNA in solvating water molecules and investigated the specific interactions between them at atomic and electronic levels using ab initio molecular simulations based on classical molecular dynamics and ab initio fragment molecular orbital methods. The results highlight the important amino acid residues of CAP for the interactions between CAP and cAMP and between CAP and DNA.