Structure models of mechanosensitive channel from accessibility data and molecular dynamics simulation

Abstract

The mechanosensitive channel of large conductance (MscL) is a homopentameric membrane protein that serves as effective osmotic safety valves in prokaryotes. It senses and transduces mechanical stimuli into protein motion. MscL is specifically designed to change its conformation in response to changes in membrane tension. In this study, two different EPR dataset were used in modeling the Escherichia coli MscL channel in its closed (cl-ecoMscL) and intermediate (in-ecoMscL) conformations through paDSAR, an experimentally restrained molecular dynamics simulation method. The in-ecoMscL model is in overall very similar to the cl-ecoMscL, suggesting the model may be correspond to pre-expanded closed state. Structure comparison between cl-ecoMscL and in-ecoMscL revealed the major transmembrane (TM) movement is located near the hydrophobic gate residues: Leu19 and Val23. To investigate structure and dynomics properties of the protein, 100ns molecular dynamics (MD) simulations of the closed and intermediate state conformations were performed in palmitoyl-oleoyl-phosphatidyl cholines bilayer and dilauroyl-glycero-phosphocholines bilayer, respectively. The results show structure stability of MscL during the course of MD simulations. The relative mobility of TM1 and TM2 segments is consistent with the experimental mobility data. The bilayer thickness change observed from the MD simulations indicated the protein- induced bilayer deformation due to the effect of hydrophobic mismatch.