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

Bharatham N, Chi SW, Yoon HS - PLoS ONE (2011)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University, Singapore.

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.

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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.
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pone-0026014-g004: 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.

Mentions: Binding free energy calculations were carried out for MDM2/p53 complex to better understand the interaction pattern of p53 with MDM2 as well as to unveil the hot spot residues of p53 which are common in complex formation with MDM2 and Bcl-XL. This simulation results also allowed us to compare with previous computational studies and benchmark our MD simulation protocol. For this purpose we have opted MM/GBSA method to calculate the binding free energy of MDM2/p53 complex. The ΔGbind of this complex was computed as −11.3 kcal/mol (Table 2 and Table 3) which is close to experimental binding free energy (−6.4 to −9.0 kcal/mol) [60], [61] and other computational studies estimates −6.9 to −16 kcal/mol [44]–[48]. The residue level contribution was carried out to extract the key residues information from both protein (MDM2) and peptide. The results suggest that the residues, F19, W23 and L26 of p53 contribute more in binding and moreover F19 is better contributor for binding than W23 (Table 4), which is consistent with previous computational observations [48]. Several hydrophobic and one or two hydrophilic MDM2 residues which are important in complex formation were also identified (Figure 4A).


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

Bharatham N, Chi SW, Yoon HS - PLoS ONE (2011)

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.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3198449&req=5

pone-0026014-g004: 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.
Mentions: Binding free energy calculations were carried out for MDM2/p53 complex to better understand the interaction pattern of p53 with MDM2 as well as to unveil the hot spot residues of p53 which are common in complex formation with MDM2 and Bcl-XL. This simulation results also allowed us to compare with previous computational studies and benchmark our MD simulation protocol. For this purpose we have opted MM/GBSA method to calculate the binding free energy of MDM2/p53 complex. The ΔGbind of this complex was computed as −11.3 kcal/mol (Table 2 and Table 3) which is close to experimental binding free energy (−6.4 to −9.0 kcal/mol) [60], [61] and other computational studies estimates −6.9 to −16 kcal/mol [44]–[48]. The residue level contribution was carried out to extract the key residues information from both protein (MDM2) and peptide. The results suggest that the residues, F19, W23 and L26 of p53 contribute more in binding and moreover F19 is better contributor for binding than W23 (Table 4), which is consistent with previous computational observations [48]. Several hydrophobic and one or two hydrophilic MDM2 residues which are important in complex formation were also identified (Figure 4A).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University, Singapore.

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.

Show MeSH