Molecular Dynamics Simulations of Caveolin-1 in Membrane Bilayers

Abstract

Caveolin which is found in caveolae is an integral membrane protein. Caveolin is thought to induce membrane curvature and is involved in many crucial cell functions such as endocytosis. Its membrane-embedded domain contains two helices (TM1 and TM2) connected by a three-residue linker, and both its N- and C-termini are exposed to the cytoplasm. Since there is no portion of caveolin that protrudes to the opposite side of the membrane, caveolin is postulated to adopt a horseshoe configuration. Despite considerable efforts, the structure of caveolin in a bilayer remains elusive. This work aims to characterize the structure and dynamics of caveolin-1 (D82 to S136; Cav182-136) in a DMPC bilayer using molecular dynamics (MD) simulations. In Cav182-136, TM1 and TM2 corresponds to A87−F107 and L111−A129, respectively. To explore a sufficiently large configurational space of Cav182-136, 50 independent initial models (10 for each of 45°, 55°, 65°, 75°, 86° TM1-TM2 angles) were built and each of them was placed in a DMPC bilayer with a 0.15M KCl solution using the CHARMM-GUI Membrane Builder. The TM1-TM2 linker (G108, I109, and P110) in each of the systems was randomly placed in between Z = −5 to 5 A. A 50-ns production was performed for each system using CHARMM, and the results are presented and discussed in terms of (1) the orientation of Cav182-136 and its fluctuation [tilt angle of TM1-TM2 plane, TM1-TM2 angle, TM1 and TM2 tilt angle, insertion depth of the TM1-TM2 linker and four Trp residues: 85, 98, 115, 128], (2) TM1-TM2 contact residues, (3) Cav182-136−bilayer interactions, and (4) bilayer shapes.