論文 - 千見寺　浄慈

Roles of DNA Looping in Enhancer-Blocking Activity 査読有り

Naoko Tokuda, Masaki Sasai, George Chikenji

Biophysical Journal   100 巻 ( 1 ) 頁： 126-134   2011年1月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

*Folding energy landscape and network dynamics of small globular proteins 査読有り

Naoto Hori, George Chikenji, R. Stephen Berry, and Shoji Takada

  106 巻 ( 1 ) 頁： 73-78   2009年1月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The folding energy landscape of proteins has been suggested to be funnel-like with some degree of ruggedness on the slope. How complex the landscape, however, is still rather unclear. Many experiments for globular proteins suggested relative simplicity, whereas molecular simulations of shorter peptides implied more complexity. Here, by using complete conformational sampling of 2 globular proteins, protein G and src SH3 domain and 2 related random peptides, we investigated their energy landscapes, topological properties of folding networks, and folding dynamics. The projected energy surfaces of globular proteins were funneled in the vicinity of the native but also have other quite deep, accessible minima, whereas the randomized peptides have many local basins, including some leading to seriously misfolded forms. Dynamics in the denatured part of the network exhibited basin-hopping itinerancy among many conformations, whereas the protein reached relatively well-defined final stages that led to their native states. We also found that the folding network has the hierarchic nature characterized by the scale-free and the small-world properties.

*In silico chaperonin-like cycle helps folding of proteins for structure prediction 査読有り

Tadaomi Furuta, Yoshimi Fujitsuka, George Chikenji and Shoji Takada

Biophys. J.   94 巻 ( 7 ) 頁： 2558-2565   2008年4月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Currently, one of the most serious problems in protein-folding simulations for de novo structure prediction is conformational sampling of medium-to-large proteins. In vivo, folding of these proteins is mediated by molecular chaperones. Inspired by the functions of chaperonins, we designed a simple chaperonin-like simulation protocol within the framework of the standard fragment assembly method: in our protocol, the strength of the hydrophobic interaction is periodically modulated to help the protein escape from misfolded structures. We tested this protocol for 38 proteins and found that, using a certain defined criterion of success, our method could successfully predict the native structures of 14 targets, whereas only those of 10 targets were successfully predicted using the standard protocol. In particular, for non-alpha-helical proteins, our method yielded significantly better predictions than the standard approach. This chaperonin-inspired protocol that enhanced de novo structure prediction using folding simulations may, in turn, provide new insights into the working principles underlying the chaperonin system.

*Shaping up the protein folding funnel by local interaction: lesson from a structure prediction study 査読有り

George Chikenji, Yoshimi Fujitsuka and Shoji Takada

Proc. Natl. Acad. Sci. USA   103 巻 ( 9 ) 頁： 3141-3146   2006年2月

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Predicting protein tertiary structure by folding-like simulations is one of the most stringent tests of how much we understand the principle of protein folding. Currently, the most successful method for folding-based structure prediction is the fragment assembly (FA) method. Here, we address why the FA method is so successful and its lesson for the folding problem. To do so, using the FA method, we designed a structure prediction test of "chimera proteins." In the chimera proteins, local structural preference is specific to the target sequences, whereas nonlocal interactions are only sequence-independent compaction forces. We find that these chimera proteins can find the native folds of the intact sequences with high probability indicating dominant roles of the local interactions. We further explore roles of local structural preference by exact calculation of the HP lattice model of proteins. From these results, we suggest principles of protein folding: For small proteins, compact structures that are fully compatible with local structural preference are few, one of which is the native fold. These local biases shape up the funnel-like energy landscape.

*SimFold energy function for de novo protein structure prediction: Consensus with Rosetta 査読有り

Yoshimi Fujitsuka, George Chikenji, and Shoji Takada

Proteins: Struct. Funct. Bioinfo.   62 巻 ( 2 ) 頁： 381-398   2006年2月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Predicting protein tertiary structures by in silico folding is still very difficult for proteins that have new folds. Here, we developed a coarse-grained energy function, SimFold, for de novo structure prediction, performed a benchmark test of prediction with fragment assembly simulations for 38 test proteins, and proposed consensus prediction with Rosetta. The SimFold energy consists of many terms that take into account solvent-induced effects on the basis of physicochemical consideration. In the benchmark test, SimFold succeeded in predicting native structures within 6.5 A for 12 of 38 proteins; this success rate was the same as that by the publicly available version of Rosetta (ab initio version 1.2) run with default parameters. We investigated which energy terms in SimFold contribute to structure prediction performance, finding that the hydrophobic interaction is the most crucial for the prediction, whereas other sequence-specific terms have weak but positive roles. In the benchmark, well-predicted proteins by SimFold and by Rosetta were not the same for 5 of 12 proteins, which led us to introduce consensus prediction. With combined decoys, we succeeded in prediction for 16 proteins, four more than SimFold or Rosetta separately. For each of 38 proteins, structural ensembles generated by SimFold and by Rosetta were qualitatively compared by mapping sampled structural space onto two dimensions. For proteins of which one of the two methods succeeded and the other failed in prediction, the former had a less scattered ensemble located around the native. For proteins of which both methods succeeded in prediction, often two ensembles were mixed up.

*Protein folding mechanisms and energy landscape of src SH3 domain studied by a structure prediction toolbox 査読有り

George Chikenji, Yoshimi Fujitsuka, Shoji Takada

CHEMICAL PHYSICS   307 巻 ( 2-3 ) 頁： 157-162   2004年12月

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

The global energy landscape of src SH3 domain is comprehensively explored and folding mechanisms are discussed by using a physico-chemical protein model and the reversible fragment assembly method. We found that the lowest energy structure found in simulations is quite similar to the native, an apparent free energy barrier exists between the denatured and native states, and the computed folding transition state ensemble is well consistent with experimental data. Interestingly, non-native alpha-helical contents are found at early stage of folding, which also seems to be consistent with a recent experiment. These results suggest that the fragment assembly method, originally developed for structure prediction, can be used for studying folding mechanisms as well.