Data Science and Learning Division, Argonne National Laboratory, Lemont, IL 60439, USA.
Consortium for Advanced Science and Engineering, University of Chicago, Chicago, IL 60637, USA.
Biomolecules. 2020 Sep 11;10(9):1308. doi: 10.3390/biom10091308.
Viral BCL2 proteins (vBCL2s) help to sustain chronic infection of host proteins to inhibit apoptosis and autophagy. However, details of conformational changes in vBCL2s that enable binding to BH3Ds remain unknown. Using all-atom, multiple microsecond-long molecular dynamic simulations (totaling 17 μs) of the murine γ-herpesvirus 68 vBCL2 (M11), and statistical inference techniques, we show that regions of M11 transiently unfold and refold upon binding of the BH3D. Further, we show that this partial unfolding/refolding within M11 is mediated by a network of hydrophobic interactions, which includes residues that are 10 Å away from the BH3D binding cleft. We experimentally validate the role of these hydrophobic interactions by quantifying the impact of mutating these residues on binding to the Beclin1/BECN1 BH3D, demonstrating that these mutations adversely affect both protein stability and binding. To our knowledge, this is the first study detailing the binding-associated conformational changes and presence of long-range interactions within vBCL2s.
病毒 BCL2 蛋白（vBCL2）有助于维持宿主蛋白的慢性感染，从而抑制细胞凋亡和自噬。然而，vBCL2 与 BH3D 结合所导致的构象变化的细节仍然未知。我们使用全原子、多微秒长的分子动力学模拟（总计 17 μs），对鼠γ疱疹病毒 68 的 vBCL2（M11）进行了研究，并运用统计推断技术，表明 M11 与 BH3D 结合时会发生瞬时展开和重新折叠。此外，我们表明，M11 内的这种部分展开/折叠是由一个疏水相互作用网络介导的，该网络包括与 BH3D 结合缝隙相距 10 Å 的残基。我们通过定量分析突变这些残基对与 Beclin1/BECN1 BH3D 结合的影响，实验验证了这些疏水相互作用的作用，证明这些突变对蛋白质稳定性和结合都有不利影响。据我们所知，这是第一个详细描述 vBCL2 内结合相关构象变化和长程相互作用的研究。
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