Ishida, H. (2014) Essential function of the N-termini tails of the proteasome for the gating mechanism revealed by molecular dynamics simulations , Proteins, 82, 1985-1999.

The proteasome is involved in the degradation of the majority of cellular proteins and plays an important role in a wide variety of biological processes from protein quality control to DNA repair, gene transcription, chromatin remodeling, cell-cycle control, signal transduction, antigen presentation, and so on. The 19S-CP-PA28 complex called a hybrid proteasome (Fig. 1) is thought to be responsible for the efficient proteolysis of the substrate, and to be involved in the immunological processing of intracellular antigens. The free-energies of the translocation of a substrate moving through the 19S-CP-PA28 complex were estimated as shown in Figure 2. From the results, a model of the entry of the substrate and the release of the products by the hybrid proteasome has been proposed (Fig. 2).

Ikebe, J., Sakuraba, S. and Kono, H. (2014) Adaptive lambda square dynamics simulation: An efficient conformational sampling method for biomolecules J Comput. Chem., 35, 39-50.

Proteins and DNAs are chainlike biomolecules consisted of amino acids and nucleotides, respectively. These chain molecules fulfill their functions by folding into the specific conformations with low free-energy. It is one of biological goals to reproduce the free-energy landscapes of biomolecules with molecular dynamics simulations. However, conventional simulation methods require enormous computational time to obtain the landscapes. Thus, we developed a novel simulation method, Adaptive Lambda Square Dynamics (ALSD) that can reproduce the landscapes faster than conventional methods. ALSD samples the various conformations fast by enhancing the potential energy fluctuation of the biomolecules. We quantitatively confirmed that ALSD reproduced the free-energy landscape of poly-lysine decapeptide faster than a conventional method (McMD).

Sunami, T. and Kono, H. (2013) Local conformational changes in the DNA interfaces of proteins. PLoS One. 2013;8(2):e56080.

Local conformational changes in the DNA interfaces of proteins. PLoS One. 2013;8(2):e56080.

When a protein binds to DNA, a conformational change is often induced so that the protein will fit into the DNA structure. Therefore, quantitative analyses were conducted to understand the conformational changes in proteins. The results showed that conformational changes in DNA interfaces are more frequent than in non-interfaces, and DNA interfaces have more conformational variations in the DNA-free form. As expected, the former indicates that interaction with DNA has some influence on protein structure. The latter suggests that the intrinsic conformational flexibility of DNA interfaces is important for adjusting their conformation for DNA. The amino acid propensities of the conformationally changed regions in DNA interfaces indicate that hydrophilic residues are preferred over the amino acids that appear in the conformationally unchanged regions. This trend is true for disordered regions, suggesting again that intrinsic flexibility is of importance not only for DNA binding but also for interactions with other molecules. These results demonstrate that fragments destined to be DNA interfaces have an intrinsic flexibility and are composed of amino acids with the capability of binding to DNA. This information suggests that the prediction of DNA binding sites may be improved by the integration of amino acid preference for DNA and one for disordered regions.