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. 2011;6(10):e26014.
doi: 10.1371/journal.pone.0026014. Epub 2011 Oct 19.

Molecular basis of Bcl-X(L)-p53 interaction: insights from molecular dynamics simulations (VSports注册入口)

Nagakumar Bharatham  1 , Seung-Wook Chi, Ho Sup Yoon
Affiliations

VSports app下载 - Molecular basis of Bcl-X(L)-p53 interaction: insights from molecular dynamics simulations

Nagakumar Bharatham (V体育安卓版) et al. PLoS One. 2011.

Abstract

Bcl-X(L), an antiapoptotic Bcl-2 family protein, plays a central role in the regulation of the apoptotic pathway. Heterodimerization of the antiapoptotic Bcl-2 family proteins with the proapoptotic family members such as Bad, Bak, Bim and Bid is a crucial step in the apoptotic regulation. In addition to these conventional binding partners, recent evidences reveal that the Bcl-2 family proteins also interact with noncanonical binding partners such as p53. Our previous NMR studies showed that Bcl-X(L): BH3 peptide and Bcl-X(L): SN15 peptide (a peptide derived from residues S15-N29 of p53) complex structures share similar modes of bindings. To further elucidate the molecular basis of the interactions, here we have employed molecular dynamics simulations coupled with MM/PBSA approach. Bcl-X(L) and other Bcl-2 family proteins have 4 hydrophobic pockets (p1-p4), which are occupied by four systematically spaced hydrophobic residues (h1-h4) of the proapoptotic Bad and Bak BH3 peptides. We observed that three conserved hydrophobic residues (F19, W23 and L26) of p53 (SN15) peptide anchor into three hydrophobic pockets (p2-p4) of Bcl-X(L) in a similar manner as BH3 peptide. Our results provide insights into the novel molecular recognition by Bcl-X(L) with p53. VSports手机版.

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Conflict of interest statement (VSports注册入口)

Competing Interests: The authors have declared that no competing interests exist.

"V体育官网" Figures

Figure 1
Figure 1. Binding orientation and sequence comparison of SN15 with BH3 peptides.
The interaction pattern of Bcl-XL and Bad (A), Bak (B), SN15 (C) was shown. All the three peptides represented as cartoon and Bcl-XL as surface. Hydrophobic residues of the peptides which occupy the four hydrophobic pockets (p1–p4) are highlighted by sticks and labeled accordingly. All the three peptides (Bad, Bak and SN15) superimposed and the important interacting regions of Bcl-XL such as BH1, BH2 and BH3 are highlighted with magenta, red and gray, respectively (D). Shown is sequence comparison between SN15 and Bad and Bak. Four important binding points (h1–h4) are highlighted by green boxes, identical residues and conserved residues are highlighted by red and yellow colors, respectively (E).
Figure 2
Figure 2. RMSD plots for five MD simulations.
The Root mean square deviation (RMSD) of backbone atoms were shown with respect to initial minimized structure for all the five simulations such as MDM2/p53 (A), Bcl-XL/SN15 (B), Bcl-XL/Bad (C), Bcl-XL/Bak (D), and Bcl-XL/SN15W23A (E).
Figure 3
Figure 3. Stability of secondary structural features of Bcl-XL/SN15 complex.
Secondary structural characteristics were calculated using DSSP for total simulation to understand the stability and changes for the Bcl-XL/SN15 complex. The initial (7 residues) and final (9 residues) helix length of the SN15 are represented with starting and ending residues of helix and highlighted by arrows. Initial and final frames of the protein represented as cartoon model and labeled.
Figure 4
Figure 4. Major contributing residues of MDM2 and Bcl-XL for complex formation with SN15 and BH3 peptides.
Pictorial representation of important residues of MDM2 for complex formation with p53 (A). The p53 peptide is shown in magenta cartoon and MDM2 protein is highlighted by surface representation. The major contributors from both protein and peptide are represented by sticks and labeled. The Bcl-XL protein and peptides Bad (B), Bak (C), SN15 (D) are represented as cartoon model and major contributing residues are shown as sticks. Important interacting regions of Bcl-XL such as BH1, BH2 and BH3 are highlighted as magenta, red and gray, respectively.
Figure 5
Figure 5. Hydrophobic and charged surface of Bcl-XL.
The shallow hydrophobic pocket of Bcl-XL is shown with yellow color, positive and negatively charged residues present on the walls of the pocket represented with blue and red, respectively. The hydrophobic residues of peptides h1–h4 of Bad (A), Bak (B) and h2–h4 of SN15 (C) are highlighted as sticks which lock with hydrophobic pockets of Bcl-XL. Complimentary charged residues on Bad (D), Bak (E), SN15 (F) are highlighted as sticks and labeled accordingly.
Figure 6
Figure 6. Hydrogen bonding pattern of p53 tryptophan residue.
W23 residue of p53 or SN15 forms stable hydrogen bonding interaction with main chain carbonyl of E96 of Bcl-XL are shown (A). Hydrogen bond interaction between W23 of p53 and main chain carbonyl of L54 residue of MDM2 are shown (B). Hydrogen bond represented with black dotted line.
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