Atomistic Insights into TRPC6/Caveolin-1 Interactions Interface via All- Atom Molecular Dynamics Simulations: Structural and Energetic Basis for Selective Modulation
- 1University of Texas Medical Branch
Abstract
The molecular determinants governing TRPC6 stabilization and its interaction with caveolin-1 (CAV1) remain poorly defined, despite their critical role in caveolae organization and signaling. The absence of atomistic structural models has hindered a mechanistic understanding of how TRPC6 is recruited to, and stabilized within, caveolar microdomains. Here, we combine all-atom molecular dynamics simulations with MM/PBSA calculations to characterize the TRPC6–CAV1 complex at atomic resolution. To preserve a biologically realistic membrane environment, harmonic restraints were applied to transmembrane and membrane-embedded regions of both proteins, while the cytosolic TRPC6 N-terminus and solvent-exposed edges of the CAV1 scaffolding domain were kept fully flexible, allowing the putative caveolin-binding motif to explore conformational space and form dynamic contacts. This protocol maintained overall structural integrity while capturing physiologically relevant flexibility at the interaction surface. MM/PBSA analysis revealed a highly favorable binding free energy (ΔG_binding = −255.9 ± 1.6 kJ/mol), dominated by electrostatic contributions and reinforced by hydrophobic and aromatic interactions. Per-residue energy decomposition identified an acidic patch in TRPC6 (residues 30–41) that engages a complementary basic, amphipathic segment in CAV1 (residues 85–106), defining a cooperative, reversible binding interface. These findings provide the first atomistic description of TRPC6 recruitment by CAV1 and establish a quantitative framework for the rational design of strategies to selectively modulate this interaction. Highlight Established the first atomistic model of the TRPC6–CAV1 interaction in caveolae Combined all-atom MD simulations with restrained membrane-embedded protein models Interface analysis shows reversible noncovalent binding via transient H-bonds and salt bridges MM/PBSA revealed strong electrostatic-driven binding of the TRPC6–CAV1 complex Identified an acidic TRPC6 N-terminal hotspot engaging a basic amphipathic CAV1 region Graphical Abstract
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BibTeX
@misc{polat2026atomistic,
title = {{Atomistic Insights into TRPC6/Caveolin-1 Interactions Interface via All- Atom Molecular Dynamics Simulations: Structural and Energetic Basis for Selective Modulation}},
author = {O. K. Polat and S. Bazsefidpar and A. Rodriguez and M. X. Mori and H. Mosadeghi and A. K. Israni and K. M. Koss},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.09.750526},
url = {https://www.biorxiv.org/content/10.64898/2026.09.09.750526v1},
note = {Public domain},
}
RIS
TY - UNPB
TI - Atomistic Insights into TRPC6/Caveolin-1 Interactions Interface via All- Atom Molecular Dynamics Simulations: Structural and Energetic Basis for Selective Modulation
AU - O. K. Polat
AU - S. Bazsefidpar
AU - A. Rodriguez
AU - M. X. Mori
AU - H. Mosadeghi
AU - A. K. Israni
AU - K. M. Koss
PY - 2026
DA - 2026/09/09
PB - bioRxiv
DO - 10.64898/2026.09.09.750526
UR - https://www.biorxiv.org/content/10.64898/2026.09.09.750526v1
AB - The molecular determinants governing TRPC6 stabilization and its interaction with caveolin-1 (CAV1) remain poorly defined, despite their critical role in caveolae organization and signaling. The absence of atomistic structural models has hindered a mechanistic understanding of how TRPC6 is recruited to, and stabilized within, caveolar microdomains. Here, we combine all-atom molecular dynamics simulations with MM/PBSA calculations to characterize the TRPC6–CAV1 complex at atomic resolution. To preserve a biologically realistic membrane environment, harmonic restraints were applied to transmembrane and membrane-embedded regions of both proteins, while the cytosolic TRPC6 N-terminus and solvent-exposed edges of the CAV1 scaffolding domain were kept fully flexible, allowing the putative caveolin-binding motif to explore conformational space and form dynamic contacts. This protocol maintained overall structural integrity while capturing physiologically relevant flexibility at the interaction surface. MM/PBSA analysis revealed a highly favorable binding free energy (ΔG_binding = −255.9 ± 1.6 kJ/mol), dominated by electrostatic contributions and reinforced by hydrophobic and aromatic interactions. Per-residue energy decomposition identified an acidic patch in TRPC6 (residues 30–41) that engages a complementary basic, amphipathic segment in CAV1 (residues 85–106), defining a cooperative, reversible binding interface. These findings provide the first atomistic description of TRPC6 recruitment by CAV1 and establish a quantitative framework for the rational design of strategies to selectively modulate this interaction. Highlight Established the first atomistic model of the TRPC6–CAV1 interaction in caveolae Combined all-atom MD simulations with restrained membrane-embedded protein models Interface analysis shows reversible noncovalent binding via transient H-bonds and salt bridges MM/PBSA revealed strong electrostatic-driven binding of the TRPC6–CAV1 complex Identified an acidic TRPC6 N-terminal hotspot engaging a basic amphipathic CAV1 region Graphical Abstract
ER -