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Transient Unfolding and Long-Range Interactions in Viral BCL2 M11 Enable Binding to the BECN1 BH3 Domain

Ramanathan, Arvind and Parvatikar, Akash and Chennubhotla, Srinivas C. and Mei, Yang and Sinha, Sangita C. (2020) Transient Unfolding and Long-Range Interactions in Viral BCL2 M11 Enable Binding to the BECN1 BH3 Domain. Biomolecules, 10 (9). p. 1308. ISSN 2218-273X

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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.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Ramanathan, Arvind
Chennubhotla, Srinivas C.chakracs@pitt.educhakracs
Mei, Yang
Sinha, Sangita C.
Date: 11 September 2020
Date Type: Publication
Journal or Publication Title: Biomolecules
Volume: 10
Number: 9
Publisher: MDPI AG
Page Range: p. 1308
DOI or Unique Handle: 10.3390/biom10091308
Schools and Programs: School of Medicine > Computational and Systems Biology
Refereed: Yes
Uncontrolled Keywords: BCL2, BECN1, intrinsic disorder, transient folding, machine learning
ISSN: 2218-273X
Official URL:
Funders: Argonne Laboratory Directed Research and Development Computing Expedition, National Institutes of Health, National Science Foundation
Article Type: Research Article
Date Deposited: 26 May 2021 20:20
Last Modified: 26 May 2021 20:20


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