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池部 仁善; 櫻庭 俊; 河野 秀俊
no journal, ,
A nucleosome, 146 or 147 base-pair DNA wrapped around a histone octamer composed of two copies of each H3, H4, H2A, and H2B histone proteins, is a compact unit structure to store eukaryotic DNA into the cell nucleus. Although the X-ray conformations of the core region have been already determined, the conformations of the disordered histone terminal regions (histone tails) remain poorly understood. Recent experimental evidences suggest that chemical modifications on the histone tails regulate DNA functions, such as transcription, duplication, and splicing. To understand the regulation mechanism, it is necessary to elucidate difference between conformational states of unmodified and modified histone tails. Thus, we applied adaptive lambda square dynamics (ALSD) simulation we developed recently to investigate the conformations of H3 histone tails. ALSD dynamically scales the simulation parameters (charge, van der Walls and torsion energies) only for the histone tails during the simulations. This successfully sampled various histone tail conformations. In this poster, we introduce the ALSD simulation results and the differences in conformational ensembles between unmodified and acetylated H3 histone tails.
石田 恒
no journal, ,
Proteasome is involved in the degradation of proteins. Proteasome activators bind to the proteasome core particle (CP) and facilitate opening a gate of the CP, where Tyr8 and Asp9 in the N-termini tails of the CP form the ordered open gate. In a double mutant (Tyr8Gly/Asp9Gly), the N-termini tails are disordered and the stabilized open-gate conformation cannot be formed. To understand how proteasome is responsible for the efficient proteolysis of the substrate, four different molecular dynamics (MD) simulations were carried out: ordered- and disordered-gate models of the CP complexed with an ATP-independent PA26 and ordered- and disordered-gate models of the CP complexed with an ATP-dependent PAN-like activator. The free-energies of the translocation of a poly-peptide substrate moving through the gate were estimated. It was concluded that the dynamics of the N-termini tails entropically play a key role in the translocation of the substrate.
河野 秀俊; 櫻庭 俊; 石田 恒
no journal, ,
Eukaryotic genome is compactly stored into a tiny nucleus of cell in a form of protein-DNA complex. This protein-DNA complex is called as nucleosome which is composed of a histone octamer formed by two copies each of the four core histones H3, H4, H2A and H2B and about 150bp of DNA wrapping almost twice around the octamer. This compact form, however, has to be unwrapped in transcription, DNA duplication and DNA repair processes. To study the detailed molecular mechanism, we calculated free energy profiles for unwrapping nucleosomal DNA on H3-containg and CENP-A containing nucleosomes with adaptively biased MD and umbrella sampling. We estimated from the profiles that a cost for unwrapping the outer DNA is 0.1 to 0.4 kcal/mol/1bp, consistent with a value experimentally obtained. Compared with H3 nucleosome, the profile showed that CENP-A nucleosome was the most stable in a conformation where 15bp from each of ends were unwrapped. The detail analysis indicated that this is attributable to the difference in ability of forming hydrogen bond of alphaN helix of H3 and CENP-A.