Dynamics of Bcl-xL in Water and Membrane: Molecular Simulations

Abstract

The Bcl2 family of proteins is capable of switching the apoptotic machinery by directly controlling the release of apoptotic factors from the mitochondrial outer membrane. They have ‘pro’ and ‘anti’-apoptotic subgroups of proteins which antagonize each other’s function; however a detailed atomistic understanding of their mechanisms based on the dynamical events, particularly in the membrane, is lacking. Using molecular dynamics simulations totaling 1.6µs we outline the major differences between the conformational dynamics in water and in membrane. Using implicit models of solvent and membrane, the simulated results reveal a picture that is in agreement with the ‘hit-and run’ concept which states that BH3-only peptides displace the tail (which acts as a pseudo substrate of the protein itself) from its binding pocket; this helps the membrane association of the protein after which the BH3 peptide becomes free. From simulations, Bcl-xL appears to be auto-inhibited by its C-terminal tail that embeds into and covers the hydrophobic binding pocket. However the tail is unable to energetically compete with BH3-peptides in water. In contrast, in the membrane, neither the tail nor the BH3-peptides are stable in the binding pocket and appear to be easily dissociated off as the pocket expands in response to the hydrophobic environment. This renders the binding pocket large and open, thus receptive to interactions with other protein partners. Principal components of the motions are dramatically different in the aqueous and in the membrane environments and provide clues regarding the conformational transitions that Bcl-xL undergoes in the membrane, in agreement with the biochemical data.

Targeting γ-Herpesvirus 68 Bcl-2-mediated Down-regulation of Autophagy

“…Based on superpositions of the complexes of M11-DS peptide, M11-WT BH3 domain, and Bcl-X L -WT BH3 domain, it appears that the peptide shifts observed in the M11-DS peptide complex, which enable the G120E to interact with Arg 87 , would not be easily accommodated in Bcl-X L . For instance, an obvious steric clash would occur between the Leu 122 main chain of the shifted DS peptide and the Bcl-X L R100, whose conformation is stabilized by salt bridge networks (56). This information adds significantly to our understanding of interactions between Bcl-2 homologs and BH3 domain-containing proteins, explaining how mutated or diverse BH3 domains may be bound by one homolog and not another, thus also adding to our repertoire of information on protein-protein interactions in general.…”

“…Similarly, the next peptide residue, Val 118 , is solvent-exposed and does not interact with M11 in the WT BH3 domain complex, but a 1.3 Å C␣ shift (Fig. 5B) at this position in the DS peptide complex results in packing against M11 Tyr 56 (Fig. 6A).…”

Conformation of BCL-XL upon Membrane Integration

“…Compared to their water-soluble states, membrane-bound BCL-XL and BCL-W have been proposed to display diminished affinity for their BH3 ligands due to a loosening of the groove structure in the hydrophobic environment 26; 33; 34 . According to current models, membrane binding by water-soluble BCL-2 proteins induces major conformational changes, while BH3 ligand binding by membrane-integrated BCL-2 proteins causes ulterior structural changes and ligand release 3 .…”

Complex disruption effect of natural polyphenols on Bcl-2-Bax: molecular dynamics simulation and essential dynamics study

“…Bcl-2 family proteins are characterized by containing up to four conserved sequences of amino acids which are known as Bcl-2 homology (BH) domains (Adams & Cory, 2001;Cao, Yap, & Newell-Rogers, 2013;Czabotar, Lessene, Strasser, & Adams, 2014;Hosseini et al, 2013;Opferman & Korsmeyer, 2003). They are usually grouped into three distinct subclasses: (1) Bax and Bak (contain the BH1 to BH3 domains) that mediate apoptosis by triggering destabilization of the outer mitochondrial membrane and releasing the cytochrome c from mitochondria to the cytosol (Antignani & Youle, 2006;Green & Kroemer, 2004), (2) Bim, Bad, Puma, and Noxa (the BH3-only proteins) that communicate pro-death signals and ultimately activate downstream Bax and Bak (Kim et al, 2006;Willis et al, 2007), (3) Bcl-xL, Bcl-w, Mcl-1, A1, and Bcl-B (contain all the four BH1 to BH4 domains) that suppress the activation of Bax/Bak (Ku, Liang, Jung, & Oh, 2011;Liu, Dai, Zhu, Marrack, & Kappler, 2003;Maity, Yadav, Verma, & Dastidar, 2013;Petros et al, 2000;Sattler et al, 1997).…”