第199回自然環境論セミナー「Molecular dynamic simulations of Nuclear Receptors: Pushing the boarders of a molecular dynamics simulation」
開催について
- 日時
- 2008年11月14日 (金) 13:20～14:50
- 会場
- 神戸大学発達科学部 A325教室 (A棟3階)
- 対象
- どなたでも参加できます。
- 参加方法
- 当日、直接、会場へお越しください。
- 参加費
- 無料
- 主催
- 神戸大学発達科学部人間環境学科 自然環境論コース
- 連絡先
- メール: tanaka2@【続けて「kobe-u.ac.jp」を入力してください】 (田中 成典 (人間発達環境学研究科 人間環境学専攻))
プログラム
| 講師 | Sofia Burendahl (Karolinska Institutet) |
|---|---|
| タイトル | Molecular dynamic simulations of Nuclear Receptors: Pushing the boarders of a molecular dynamics simulation |
内容
Molecular Dynamic (MD) simulations have been successfully used to study molecular events like structural stability and molecular interaction but many of the molecular mechanism which takes place in the cell are acting on a timescale beyond the capacity of a MD simulation. Such an event is the ligand unbinding from the Nuclear Receptors (NR). The NRs functions as a transcription regulator and can be activated upon ligand binding. Consequently ligand binding and unbinding constitutes a fundamental process in the regulation of genes. Even though both biochemical and structural data of NR are available, the actual mechanism of the ligand binding/unbinding remains elusive. We have performed ligand unbinding studies on NRs with modified the MD methods (1) Random Acceleration MD (RAMD) (2) and Steered MD (SMD) (3) which speed up the timescale. The results show that agonist ligand unbinding can take place from the receptor without causing major conformational changes in the receptor, while antagonist unbinding cannot. Further on ligand selectivity and method sampling were discussed.
Allosteric properties have previously been studied with covariance correlation analysis and normal mode analysis. However, these methods requires long MD simulation trajectory to detect the signal. Recently publication presented the Anisotropic Thermal Diffusion method (4) which increases the signal-noise ratio within the protein and thus makes it possible to detect an allosteric signal. The method was used to study allosteric properties in the NR Liver X Receptor (LXR) and succeeded to map out a pathway from the AF-2 region and the ligand. The signaling pathway detected is both intra- and intermolecular and is transmitted through amino acids side chains and the backbone. Although promising results were achieved, the method contains some drawbacks which will also be discussed.
- Carlsson, P., S. Burendahl and L. Nilsson. (2006) Unbinding of retinoic acid from the retinoic acid receptor by random expulsion molecular dynamics. Biophys J 91, 3151-61.
- Ludemann, S. K., V. Lounnas and R. C. Wade. (2000) How do substrates enter and products exit the buried active site of cytochrome P450cam? 1.Random expulsion molecular dynamics investigation of ligand access channels and mechanisms. Journal of Molecular Biology 303, 797-811.
- Isralewitz, B., M. Gao and K. Schulten. (2001) Steered molecular dynamics and mechanical functions of proteins. Curr Opin Struct Biol 11, 224-30.
- Ota, N. and D. A. Agard. (2005) Intramolecular signaling pathways revealed by modeling anisotropic thermal diffusion. J Mol Biol 351, 345-54.
Updated: 2008/11/10 (Mon) 19:53