HIV-1 Nef Rewires Beclin 1 Conformational Allostery to Suppress Autophagy
- 1Computational Biophysics and CADD group, Computational and Mathematical Biology Centre (CMBC
- 2Translational Health Science and Technology Institute (THSTI
- 3Manipal Academy of Higher Education
Abstract
Understanding the relationship between protein flexibility, conformational-and dynamical-allostery drive the biological function is essential as these interconnected features orchestrate biochemical processes required for biological activity. Protein-protein interactions (PPIs) are central to cellular signalling and attractive therapeutic targets, yet their modulation remains challenging to elucidate using conventional approaches as it is highly govern via conformational transitions and allostery, yet how allosteric mechanisms diversify at PPI level to provide functional output is poorly understood. Here, we focus on Beclin 1, a key autophagy regulator that functions in a PPI-dependent manner. Autophagy is a critical cellular degradation and recycling pathway implicated in numerous human diseases including viral infection. Viruses like HIV exploit this process, where the viral protein Nef interacts with Beclin 1 to suppress autophagy and enhance viral survival. However, the structural basis of this inhibition remains unclear, likely due to the complex nature of PPI. To investigate as how Nef binding impair beclin 1 association with membrane, an integrative approach combining conventional and advanced molecular dynamics simulations was employed to capture conformational transitions and determinants which alter Beclin 1 during Nef binding from active-to-inactive state. Our results reveal that three dynamic loops of Beclin 1 undergo significant rearrangements, forming an aromatic cage that drives, a shift from active to inactive states, thereby impairing membrane binding and autophagy regulation. All together these analysis not only elucidating the critical mechanistic determinants responsible from activeto-inactive tansition, moreover, can be utilize for therapeutic intervention harnessing the typical PPIs.
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BibTeX
@misc{sarmadhikari2026hiv1,
title = {{HIV-1 Nef Rewires Beclin 1 Conformational Allostery to Suppress Autophagy}},
author = {Debapriyo Sarmadhikari and Mitul Srivastava and Shailendra Asthana},
howpublished = {ChemRxiv},
year = {2026},
month = aug,
doi = {10.26434/chemrxiv.15008086/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008086/v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - HIV-1 Nef Rewires Beclin 1 Conformational Allostery to Suppress Autophagy
AU - Debapriyo Sarmadhikari
AU - Mitul Srivastava
AU - Shailendra Asthana
PY - 2026
DA - 2026/08/31
PB - ChemRxiv
DO - 10.26434/chemrxiv.15008086/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008086/v1
AB - Understanding the relationship between protein flexibility, conformational-and dynamical-allostery drive the biological function is essential as these interconnected features orchestrate biochemical processes required for biological activity. Protein-protein interactions (PPIs) are central to cellular signalling and attractive therapeutic targets, yet their modulation remains challenging to elucidate using conventional approaches as it is highly govern via conformational transitions and allostery, yet how allosteric mechanisms diversify at PPI level to provide functional output is poorly understood. Here, we focus on Beclin 1, a key autophagy regulator that functions in a PPI-dependent manner. Autophagy is a critical cellular degradation and recycling pathway implicated in numerous human diseases including viral infection. Viruses like HIV exploit this process, where the viral protein Nef interacts with Beclin 1 to suppress autophagy and enhance viral survival. However, the structural basis of this inhibition remains unclear, likely due to the complex nature of PPI. To investigate as how Nef binding impair beclin 1 association with membrane, an integrative approach combining conventional and advanced molecular dynamics simulations was employed to capture conformational transitions and determinants which alter Beclin 1 during Nef binding from active-to-inactive state. Our results reveal that three dynamic loops of Beclin 1 undergo significant rearrangements, forming an aromatic cage that drives, a shift from active to inactive states, thereby impairing membrane binding and autophagy regulation. All together these analysis not only elucidating the critical mechanistic determinants responsible from activeto-inactive tansition, moreover, can be utilize for therapeutic intervention harnessing the typical PPIs.
ER -