Molecular Dynamic Simulation Studies on LolA and LolB Proteins in E. coli

The Lol system in E.coli is involved in localization of lipoproteins and hence is essential for survival of the organism. In this system, LolA is a periplasmic chaperone that binds to outer-membrane specific lipoproteins and transports them from inner to outer membrane through another intermediary protein, LolB. A hydrophobic lipid-binding cavity constituted by α-helices is responsible for the transfer of lipoproteins from LolA to LolB. The current study aims to investigate conformational changes observed in both these proteins during this transfer using a detailed computational approach. Structural change observed in LolA during the transition from "open to closed" conformation forms the first step in this transfer process. In our Molecular Dynamic Simulation Studies, an open structure LolA(R43L) and an in-silico point mutated structure (MsL43R) were exposed to water for 50ns to simulate the periplasmic environment. Important residues involved in these structural changes and the corresponding forces (H-bonding and hydrophobic interactions) responsible for the stability of these conformational changes are also identified. Our analysis reveals that the structural flexibility of LolA is an important factor for its role as a periplasmic chaperone. This study also elucidates the functional role played by active residues during protein-protein interactions such as LolA-Pal and LolB-Pal. The acyl binding regions of the structures were identified and compared with experimental results obtained by Nakada et al., 2009. A novel structure based drug targeting has been attempted for inhibition of LolA-PAL and LolB-PAL interactions. Globomycin and related drug molecules were used as substrates for docking to the active sites of LolA and LolB which are identified by our protein-protein interaction studies.