Authors
Polat, O. K., Bazsefidpar, S., Rodriguez, A., Mori, M. X., Mosadeghi, H., Israni, A. K., Koss, K. M.
Abstract
The molecular determinants governing TRPC6 stabilization and its interaction with caveolin1 (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 ({Delta}G-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.
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bioRxiv
The authors list and abstract were imported from bioRxiv on 11 Sep 2026.
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