Investigation of the structural and dynamical properties of human uncoupling protein 2 through molecular dynamics simulations.

Uncoupling protein 2 (UCP2) is an integral membrane protein that belongs to the family of mitochondrial anion carrier proteins. The absence of human UCP2 structure, lack of understanding of Cl ion transport mechanism in the UCP2 and the associated biological functions motivated us to model the protein and investigate its structural and dynamical properties in a realistic mitochondrial lipid membrane system. The lipid-protein and protein-protein interactions were probed since they were found to be responsible for the conformational changes of the transmembrane (TM) helices which are involved in facilitating Cl ion transport. Here, we employed multiscale molecular dynamics simulations including unbiased and biased MD for the investigation of the transport pathway in hUCP2 and interactions of the ion with TM helices within a membrane environment. We initially validated the hUCP2 model in the lipid membrane and then explored the transport pathway of Cl ion and its interaction with positive residues of TM2 helix that have been reported to play a major role in the Cl ion transport along with other TM helices of the protein. The simulation results suggest that the TM2 helix plays an important role in the formation of a stable ion channel due to the presence of arginine residues, in particular Arg88 which was found to be a key residue to maintain the channel pore through which the movement of Cl ions occurs. Based on the results, it can be said that the study provides an atomic-level description of the Cl ion transport mechanism in hUCP2 embedded in the mitochondrial lipid membrane.