Drug resistance on antibiotics is one of the most critical problems threatening global public health. The large conductance mechanosensitive channel (MscL) is a membrane protein functioning as a valve, which is found to be widely distributed in many pathogenic bacteria. By sensing membrane tension and then switching between open and close state, MscL regulates intracellular osmotic pressure as well as the rapid release of osmolarity-sustaining solutes such as potassium ion and glutamate, preventing the excessive change in cell volume and membrane ruptures. Research over the past decade has indicated MscL to be a potential antibiotic drug target. Stabilization of the open conformation (fully or partially open) of MscL with the appropriate drug to block the gating process, will facilitate the efflux of solutes from the cell as well as the influx of other drugs, promoting bacterial cell death. However, the progress of such a novel antibiotic discovery is restricted by the lack of MscL open-channel conformational information in the gating process. Several enhanced sampling algorithms in molecular dynamics simulations (MDS) have been proposed for studying the gating process and metastable open channel conformations, including steered molecular dynamics, MDS with biased potential (such as electric field mimicking laser radiation and microbubbles mimicking ultrasound), and other enhanced sampling techniques. Here, we used three methods, i.e., external electric field, microbubble, and Gaussian accelerated MD to simulate the channel opening process and identify metastable channel-open conformations through potential of mean force calculations. Based on those channel partially-open and fully-open conformations, we next conducted virtual screenings to identify small molecule drugs which can stabilize the metastable conformations of MscL protein. We are now performing a large-scale MDS to evaluate how well those small molecules promote and maintain channel-open conformations of MscL. The finding will be confirmed by MTS-PEG5000 competition assay.

Revealing open-channel structures of Ec-MscL with multiple nonequilibrium molecular dynamics simulation methods

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