Energetics of the Presequence-Binding Poses in Mitochondrial Protein Import Through Tom20

被引:10
|
作者
Komuro, Yasuaki [1 ,2 ]
Miyashita, Naoyuki [3 ]
Mori, Takaharu [3 ]
Muneyuki, Eiro [1 ]
Saitoh, Takashi [4 ]
Kohda, Daisuke [4 ]
Sugita, Yuji [2 ,3 ,5 ]
机构
[1] Chuo Univ, Grad Sch Sci & Engn, Bunkyo Ku, Tokyo 1128551, Japan
[2] RIKEN Adv Sci Inst, Wako, Saitama 3510198, Japan
[3] RIKEN Quantitat Biol Ctr, Chuo Ku, Kobe, Hyogo 6500047, Japan
[4] Kyushu Univ, Div Struct Biol, Med Inst Bioregulat, Higashi Ku, Fukuoka 8128582, Japan
[5] RIKEN Adv Inst Computat Sci, Chuo Ku, Kobe, Hyogo 6500047, Japan
来源
JOURNAL OF PHYSICAL CHEMISTRY B | 2013年 / 117卷 / 10期
关键词
FREE-ENERGY PATHS; MOLECULAR-DYNAMICS; STRING METHOD; EQUILIBRIUM; RECOGNITION; SIMULATION; CHANNEL; MODELS; WATER;
D O I
10.1021/jp400113e
中图分类号
O64 [物理化学(理论化学)、化学物理学];
学科分类号
070304 ; 081704 ;
摘要
Tom20 is located at the outer membrane of mitochondria and functions as a receptor for the N-terminal presequence of mitochondrial-precursor proteins. Recently, three atomic structures of the Tom20-presequence complex were determined using X-ray crystallography and classified into A-, M-, and Y-poses in terms of their presequence-binding modes. Combined with biochemical and NMR data, a dynamic-equilibrium model between the three poses has been proposed. To investigate this mechanism in further detail, we performed all-atom molecular dynamics (MD) simulations and replica-exchange MD (REMD) simulations of the Tom20-presequence complex in explicit water. In the REMD simulations, one major distribution and another minor one were observed in the converged free energy landscape at 300 K. In the major distribution, structures similar to A- and M-poses exist, whereas those similar to Y-pose are located in the minor one, suggesting that A-pose in solution is more stable than Y-pose. A k-means clustering algorithm revealed a new pose not yet obtained by X-ray crystallography. This structure has double salt bridges between Arg14 in the presequence and Glu78 or Glu79 in Tom20 and can explain the binding affinity of the complex in previous pull down assay experiments. Structural clustering and analyses of contacts between Tom20 and the presequence suggest smooth conformational changes from Y- to A-poses through low activation barriers. M-pose lies between Y- and A-poses as a metastable state. The REMD simulations thus provide insights into the energetics of the multiple-binding forms and help to detail the progressive conformational states in the dynamic-equilibrium model based on the experimental data.
引用
收藏
页码:2864 / 2871
页数:8
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