Coarse-Grained Molecular Dynamics Simulations RevealPotential Role of Cardiolipin in Lateral Organization of Proteorhodopsin

Proteorhodopsin (PR) is a microbial light-harvesting proton pump protein that is ubiquitous in marine ecosystems and is critical for biological solar energy conversion. A unique characteristic of PR is that its function can be directly affected by changes in the surrounding cellular membrane environment. Cardiolipin (CL) is a commonly found lipid in mitochondria and bacterial cell membranes and plays a prominent role in the function of numerous integral membrane proteins, due to its bulky conical shape and ionizable nature of its headgroup. CL can directly interact with other microbial rhodopsins and modulate their function; however, the potential role of CL in the function of PR is unclear. In this study, we used the MARTINI coarse-grained force field to characterize the interactions of CL with PR in a model bilayer via coarse-grained molecular dynamics (MD) simulations. Our simulations show that both electrostatic and nonpolar forces drive residue-specific interactions of CL with proteorhodopsin, especially for the asymmetrical −1 charge state of CL. Several CL binding sites were identified, with lipid–protein interactions occurring on the μs time scale. These binding sites are proximal to key functional areas and regions of oligomerization on PR, suggesting that CL could play a role in modulating proton pumping of proteorhodopsin.