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

<div><p>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 <i>ab initio</i> 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.</p></div

A coarse grained molecular dynamics study on the structure and stability of small-sized liposomes

<div><p>The dependence of geometric structure and thermal stability of liposomes on their component phospholipid molecules and distribution of molecules in the inner and the outer layers of the liposome is investigated by conducting molecular simulations in explicit water for the eight types of liposomes constructed from different phospholipids. Using molecular mechanics structure-relaxation based on the coarse grained (CG) model, stable structures of the solvated liposomes are obtained. In addition, the molecular dynamics (MD) simulations based on the CG model are carried out at 310 and 360 K for elucidating the change in structure of the solvated liposomes. The MD simulations reveal that liposomes having the same number of lipids (SNL) in both the inner and the outer layers keep their spherical structures even at 360 K. In particular, the SNLs composed of palmitoyloleoyl-phosphatidyl-ethanolamine1 or dimyristoylglycero-phosphatidyl-choline lipid exhibit a compact spherical shape. In contrast, liposomes having the same density of lipids in the inner and the outer layers cannot keep their spherical shapes at 360 K. The obtained results contribute toward developing novel liposomes with enhanced thermal stability.</p></div

Binding affinity between AhR and exogenous/endogenous ligands: molecular simulations and biological experiment

<div><p>Aryl hydrocarbon receptor (AhR) plays critical roles in cell differentiation, and its mechanism is controlled by exogenous and endogenous ligands. However, structures of AhR and its complex with ligand have not been determined by experimental structural biology. We here obtain stable structures of the complexes with rat AhR (rAhR) and some ligands in water by molecular simulations based on homology modelling, protein–ligand docking, classical molecular mechanics optimisation and <i>ab initio</i> fragment molecular orbital (FMO) calculations. In addition, the binding affinities and the specific interactions between rAhR and the ligands are investigated by <i>ab initio</i> FMO calculations and biological experiments. The experiments reveal the dependence of the rAhR-mediated transcriptional activation on the ligand binding. On the other hand, the results of FMO calculations elucidate that the exogenous ligands interact with many residues of rAhR, while the endogenous ligands interact specifically with a few residues, and that the side chain of Gln381 of rAhR interacts strongly with the oxygen atom located at the centre of the ligand. Furthermore, we evaluate the binding energies between rAhR and the ligands by the FMO method and compare them with the transcriptional activation obtained by the experiment.</p></div