Proton-coupled dynamics is ubiquitous in biology; however, detailed mechanisms remain elusive. In this talk, I will introduce a computer simulation tool called continuous constant pH molecular dynamics (CpHMD) and discuss its applications to advance the understanding of protein kinases and membrane transporters. Kinases are  cellular signaling molecules involved in cancer and many other diseases. CpHMD was used to reveal the nucleophilic hotspots [1] and activation conformational landscape [2]. Our work suggested a new strategy for targeted covalent inhibitor design and a paradigm shift in the mechanistic understanding of kinases. In the second part of the talk, I will discuss the CpHMD simulations that resolved the proton binding sites in the E. coli multi-drug efflux pump AcrB [3] and the activation mechanism of the E. coli proton-sodium antiporter NhaA [4]. These studies demonstrated the versatile utility of proton-coupled dynamical simulations to offer novel insights into secondary active transporters that play significant roles in human health and disease conditions but remain challenging to study experimentally.

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Faculty Host: Jianhan Chen and Elizabeth Vierling
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