Limits...
Behavior of solvent-exposed hydrophobic groove in the anti-apoptotic Bcl-XL protein: clues for its ability to bind diverse BH3 ligands from MD simulations.

Lama D, Modi V, Sankararamakrishnan R - PLoS ONE (2013)

Bottom Line: The solvent accessible surface areas of bulky hydrophobic residues in the groove are significantly buried by the loop LB connecting the helix H2 and subsequent helix.These observations help to understand how the hydrophobic patch in Bcl-XL remains stable in the solvent-exposed state.We suggest that both the destabilization of helix H2 and the conformational heterogeneity of loop LB are important factors for binding of diverse ligands in the hydrophobic groove of Bcl-XL.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences & Bioengineering, Indian Institute of Technology Kanpur, Kanpur, India.

ABSTRACT
Bcl-XL is a member of Bcl-2 family of proteins involved in the regulation of intrinsic pathway of apoptosis. Its overexpression in many human cancers makes it an important target for anti-cancer drugs. Bcl-XL interacts with the BH3 domain of several pro-apoptotic Bcl-2 partners. This helical bundle protein has a pronounced hydrophobic groove which acts as a binding region for the BH3 domains. Eight independent molecular dynamics simulations of the apo/holo forms of Bcl-XL were carried out to investigate the behavior of solvent-exposed hydrophobic groove. The simulations used either a twin-range cut-off or particle mesh Ewald (PME) scheme to treat long-range interactions. Destabilization of the BH3 domain-containing helix H2 was observed in all four twin-range cut-off simulations. Most of the other major helices remained stable. The unwinding of H2 can be related to the ability of Bcl-XL to bind diverse BH3 ligands. The loss of helical character can also be linked to the formation of homo- or hetero-dimers in Bcl-2 proteins. Several experimental studies have suggested that exposure of BH3 domain is a crucial event before they form dimers. Thus unwinding of H2 seems to be functionally very important. The four PME simulations, however, revealed a stable helix H2. It is possible that the H2 unfolding might occur in PME simulations at longer time scales. Hydrophobic residues in the hydrophobic groove are involved in stable interactions among themselves. The solvent accessible surface areas of bulky hydrophobic residues in the groove are significantly buried by the loop LB connecting the helix H2 and subsequent helix. These observations help to understand how the hydrophobic patch in Bcl-XL remains stable in the solvent-exposed state. We suggest that both the destabilization of helix H2 and the conformational heterogeneity of loop LB are important factors for binding of diverse ligands in the hydrophobic groove of Bcl-XL.

Show MeSH

Related in: MedlinePlus

Ribbon representation of Bcl-XL helical bundle structure.The major helices are labeled as H1 to H6 in this apo-structure (PDB ID: 1PQ0) and are shown in different colors. The loops (LB, LC and LD) connecting different helical segments are shown in purple color. The loop LA connecting helices H1 and H2 is not shown for clarity. Molecular plots in this figure and subsequent figures were generated using the VMD software [84].
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3585337&req=5

pone-0054397-g001: Ribbon representation of Bcl-XL helical bundle structure.The major helices are labeled as H1 to H6 in this apo-structure (PDB ID: 1PQ0) and are shown in different colors. The loops (LB, LC and LD) connecting different helical segments are shown in purple color. The loop LA connecting helices H1 and H2 is not shown for clarity. Molecular plots in this figure and subsequent figures were generated using the VMD software [84].

Mentions: It must be noted that in apo and holo structures, the disordered long loop linking the first two helices is not fully resolved and the structures were determined by deleting the C-terminal transmembrane domain [37]. The structure of the missing loop was built using the “Homology” module of InsightII suite of software (Accelrys Inc., San Diego, CA) by considering another structure of Bcl-XL complex (PDB ID: 1G5J [31]) as template. Wherever side-chain atoms are not resolved in the experimental structures, they were constructed using the “Biopolymer” module of InsightII. Residue numbers of Bcl-XL correspond to the sequence with UniProt [38] accession code Q64373. The ribbon diagram of a Bcl-XL structure with its different helices is shown in Figure 1.


Behavior of solvent-exposed hydrophobic groove in the anti-apoptotic Bcl-XL protein: clues for its ability to bind diverse BH3 ligands from MD simulations.

Lama D, Modi V, Sankararamakrishnan R - PLoS ONE (2013)

Ribbon representation of Bcl-XL helical bundle structure.The major helices are labeled as H1 to H6 in this apo-structure (PDB ID: 1PQ0) and are shown in different colors. The loops (LB, LC and LD) connecting different helical segments are shown in purple color. The loop LA connecting helices H1 and H2 is not shown for clarity. Molecular plots in this figure and subsequent figures were generated using the VMD software [84].
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585337&req=5

pone-0054397-g001: Ribbon representation of Bcl-XL helical bundle structure.The major helices are labeled as H1 to H6 in this apo-structure (PDB ID: 1PQ0) and are shown in different colors. The loops (LB, LC and LD) connecting different helical segments are shown in purple color. The loop LA connecting helices H1 and H2 is not shown for clarity. Molecular plots in this figure and subsequent figures were generated using the VMD software [84].
Mentions: It must be noted that in apo and holo structures, the disordered long loop linking the first two helices is not fully resolved and the structures were determined by deleting the C-terminal transmembrane domain [37]. The structure of the missing loop was built using the “Homology” module of InsightII suite of software (Accelrys Inc., San Diego, CA) by considering another structure of Bcl-XL complex (PDB ID: 1G5J [31]) as template. Wherever side-chain atoms are not resolved in the experimental structures, they were constructed using the “Biopolymer” module of InsightII. Residue numbers of Bcl-XL correspond to the sequence with UniProt [38] accession code Q64373. The ribbon diagram of a Bcl-XL structure with its different helices is shown in Figure 1.

Bottom Line: The solvent accessible surface areas of bulky hydrophobic residues in the groove are significantly buried by the loop LB connecting the helix H2 and subsequent helix.These observations help to understand how the hydrophobic patch in Bcl-XL remains stable in the solvent-exposed state.We suggest that both the destabilization of helix H2 and the conformational heterogeneity of loop LB are important factors for binding of diverse ligands in the hydrophobic groove of Bcl-XL.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences & Bioengineering, Indian Institute of Technology Kanpur, Kanpur, India.

ABSTRACT
Bcl-XL is a member of Bcl-2 family of proteins involved in the regulation of intrinsic pathway of apoptosis. Its overexpression in many human cancers makes it an important target for anti-cancer drugs. Bcl-XL interacts with the BH3 domain of several pro-apoptotic Bcl-2 partners. This helical bundle protein has a pronounced hydrophobic groove which acts as a binding region for the BH3 domains. Eight independent molecular dynamics simulations of the apo/holo forms of Bcl-XL were carried out to investigate the behavior of solvent-exposed hydrophobic groove. The simulations used either a twin-range cut-off or particle mesh Ewald (PME) scheme to treat long-range interactions. Destabilization of the BH3 domain-containing helix H2 was observed in all four twin-range cut-off simulations. Most of the other major helices remained stable. The unwinding of H2 can be related to the ability of Bcl-XL to bind diverse BH3 ligands. The loss of helical character can also be linked to the formation of homo- or hetero-dimers in Bcl-2 proteins. Several experimental studies have suggested that exposure of BH3 domain is a crucial event before they form dimers. Thus unwinding of H2 seems to be functionally very important. The four PME simulations, however, revealed a stable helix H2. It is possible that the H2 unfolding might occur in PME simulations at longer time scales. Hydrophobic residues in the hydrophobic groove are involved in stable interactions among themselves. The solvent accessible surface areas of bulky hydrophobic residues in the groove are significantly buried by the loop LB connecting the helix H2 and subsequent helix. These observations help to understand how the hydrophobic patch in Bcl-XL remains stable in the solvent-exposed state. We suggest that both the destabilization of helix H2 and the conformational heterogeneity of loop LB are important factors for binding of diverse ligands in the hydrophobic groove of Bcl-XL.

Show MeSH
Related in: MedlinePlus