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BIM Binding Remotely Regulates BAX Activation: Insights from the Free Energy Landscapes
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2018-01-23 00:00:00 , DOI: 10.1021/acs.jcim.7b00628 Souvik Sinha 1 , Atanu Maity 1 , Shubhra Ghosh Dastidar 1
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2018-01-23 00:00:00 , DOI: 10.1021/acs.jcim.7b00628 Souvik Sinha 1 , Atanu Maity 1 , Shubhra Ghosh Dastidar 1
Affiliation
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Activation of the pro-apoptotic BAX protein, a BCL-2 family member, is known to trigger apoptosis by forming pores in the mitochondrial outer membrane (MOM). While in the cytosol, release of its transmembrane C-terminal helix (called α9 helix) from a well-characterized binding pocket (BC groove) and subsequent permeabilization of the MOM are understood to be the initiating events of the activation. Concerning what initiates BAX activation, so far one plausible suggestion has been that the transient attachment of BH3-only peptide at a distal site from the BC groove triggers the activation process. Yet how this pivotal step displaces α9 from the BC groove has remained poorly understood. Using a combination of standard molecular dynamics and enhanced sampling methods, the energy landscape of BIM (BH3-only peptide) induced BAX activation has been computed, and the molecular origin of those events is hereby reported in atomistic detail. The simulated transition pathway of α9 release reveals that BIM subdues the energetic cost of the process by reducing the activation energy barrier to some extent but mostly by minimizing the free energy difference between the active (α9-released) and inactive (α9-bound) states. Interestingly, the flexibility of the α9 helix itself plays a decisive role in this mechanism. The impact of BIM encounter at the distal site is found to propagate to the α9 (BC groove bound) mostly through conserved pathways of residue level interactions. Overall, the thermodynamic basis of the “hit-and-run” mechanism for activation of the BCL-2 family is presented reconciling the available biochemical observations.
中文翻译：
BIM绑定远程调节BAX激活：来自自由能源格局的见解
已知促凋亡BAX蛋白（一种BCL-2家族成员）的激活可通过在线粒体外膜（MOM）中形成孔来触发凋亡。当处于胞质溶胶中时，将其跨膜C末端螺旋（称为α9螺旋）从一个充分表征的结合口袋（BC凹槽）中释放出来，并将其随后的MOM透化视为激活的起始事件。关于启动BAX激活的原因，到目前为止，一个似乎合理的建议是，仅BH3肽在BC沟末端位置的瞬时附着会触发激活过程。然而，该枢转台阶如何从BC凹槽中移出α9仍然知之甚少。结合使用标准分子动力学和增强的采样方法，已计算出BIM（仅BH3肽）诱导的BAX活化的能量分布，并据此详细报道了这些事件的分子起源。模拟的α9释放过渡路径表明，BIM通过在某种程度上降低活化能垒来减轻过程的能源成本，但主要是通过最小化活性状态（释放α9的状态）和非活性状态（与α9结合的状态）之间的自由能差来解决的。有趣的是，α9螺旋本身的柔韧性在该机制中起着决定性的作用。人们发现，BIM在远端部位的影响主要通过残基水平相互作用的保守途径传播至α9（BC沟界）。全面的，
更新日期：2018-01-23
中文翻译：
BIM绑定远程调节BAX激活：来自自由能源格局的见解
已知促凋亡BAX蛋白（一种BCL-2家族成员）的激活可通过在线粒体外膜（MOM）中形成孔来触发凋亡。当处于胞质溶胶中时，将其跨膜C末端螺旋（称为α9螺旋）从一个充分表征的结合口袋（BC凹槽）中释放出来，并将其随后的MOM透化视为激活的起始事件。关于启动BAX激活的原因，到目前为止，一个似乎合理的建议是，仅BH3肽在BC沟末端位置的瞬时附着会触发激活过程。然而，该枢转台阶如何从BC凹槽中移出α9仍然知之甚少。结合使用标准分子动力学和增强的采样方法，已计算出BIM（仅BH3肽）诱导的BAX活化的能量分布，并据此详细报道了这些事件的分子起源。模拟的α9释放过渡路径表明，BIM通过在某种程度上降低活化能垒来减轻过程的能源成本，但主要是通过最小化活性状态（释放α9的状态）和非活性状态（与α9结合的状态）之间的自由能差来解决的。有趣的是，α9螺旋本身的柔韧性在该机制中起着决定性的作用。人们发现，BIM在远端部位的影响主要通过残基水平相互作用的保守途径传播至α9（BC沟界）。全面的，
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