Dynamics of Bcl-xL in water and membrane : molecular simulations
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...
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sg-ntu-dr.10356-958702023-02-28T17:04:09Z Dynamics of Bcl-xL in water and membrane : molecular simulations Maity, Atanu. Yadav, Seema. Verma, Chandra S. Dastidar, Shubhra Ghosh. Fraternali, Franca. School of Biological Sciences DRNTU::Science::Biological sciences 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. Published version 2014-01-03T03:20:51Z 2019-12-06T19:22:33Z 2014-01-03T03:20:51Z 2019-12-06T19:22:33Z 2013 2013 Journal Article Maity, A., Yadav, S., Verma, C. S., & Dastidar, S. G. (2013). Dynamics of Bcl-xL in water and membrane : molecular simulations. PLoS ONE, 8(10), e76837-. 1932-6203 https://hdl.handle.net/10356/95870 http://hdl.handle.net/10220/18381 10.1371/journal.pone.0076837 24116174 en PLoS ONE © 2013 The Authors. This paper was published in PLoS ONE and is made available as an electronic reprint (preprint) with permission of the authors. The paper can be found at the following official DOI: [http://dx.doi.org/10.1371/journal.pone.0076837]. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper is prohibited and is subject to penalties under law. application/pdf |
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DRNTU::Science::Biological sciences Maity, Atanu. Yadav, Seema. Verma, Chandra S. Dastidar, Shubhra Ghosh. Dynamics of Bcl-xL in water and membrane : molecular simulations |
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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. |
author2 |
Fraternali, Franca. |
author_facet |
Fraternali, Franca. Maity, Atanu. Yadav, Seema. Verma, Chandra S. Dastidar, Shubhra Ghosh. |
format |
Article |
author |
Maity, Atanu. Yadav, Seema. Verma, Chandra S. Dastidar, Shubhra Ghosh. |
author_sort |
Maity, Atanu. |
title |
Dynamics of Bcl-xL in water and membrane : molecular simulations |
title_short |
Dynamics of Bcl-xL in water and membrane : molecular simulations |
title_full |
Dynamics of Bcl-xL in water and membrane : molecular simulations |
title_fullStr |
Dynamics of Bcl-xL in water and membrane : molecular simulations |
title_full_unstemmed |
Dynamics of Bcl-xL in water and membrane : molecular simulations |
title_sort |
dynamics of bcl-xl in water and membrane : molecular simulations |
publishDate |
2014 |
url |
https://hdl.handle.net/10356/95870 http://hdl.handle.net/10220/18381 |
_version_ |
1759853115300904960 |