Thermodynamic Characterization of Large-Conductance Mechanosensitive Channel Activation

Mahmoud Moradi, University of Arkansas

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Mahmoud Moradi, Seyed Hamid Tabari, Vivek Govind Kumar, Dylan Ogden, Adithya Polasa, Elonay Yehualashet, UGOCHI ISU, Tariq Salem, Ashkan Fakharzadeh Ghaan

We employ all-atom molecular dynamics (MD) simulations along with novel enhanced sampling techniques to characterize large-scale conformational changes of mechanosensitive channel of large conductance (MscL) and its interactions with its candidate modulators. Bacterial MscL is a model system for the study of mechanosensation. Understanding MscL conformational dynamics has specific biomedical applications as well. The high level of conservation of MscL in bacteria and its absence from the human and animal genomes make MscL an attractive drug target for novel antibiotics. MscL has been proposed to be used as a liposomal drug delivery nanovalve. By engineering, MscL can become pH-activated to release the drug when it senses the low pH of the tumor microenvironment. This project aims at elucidating conformational landscape of MscL at the molecular level, employing ensemble-based enhanced sampling techniques that require the execution of hundreds of MD simulations in parallel, which is only possible using large supercomputers.