After a year-long remote study in China, I finally arrived at U.S. and met with Chen lab members! 
Thanks to Erik and Xiping’s help. In order to get me to Amherst, they rented a car. They also shared many useful tips about living in UMass. We quickly got familiar with each other and now we are good friends. Many thanks to them again! Without you guys, the journey would never be so smooth and interesting.
In this short review, we summarize recent progresses toward understanding the structural basis of TRP channel function, as well as potential ligand binding sites that could be targeted for therapeutics. 
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Transmembrane ion channels frequently regulate ion permeation by forming bundle crossing of the pore-lining helices when deactivated. The resulting physical constriction is believed to serve as the de facto gate that imposes the major free energy barrier to ion permeation. Intriguingly, many ion channels also contain highly hydrophobic inner pores enclosed by bundle crossing, which can undergo spontaneous dewetting and give rise to a “vapor barrier” to block ion flow even in the absence of physical constriction. Using atomistic simulations, we show that hydrophobic gating and bundle-crossing mechanisms co-exist and complement one and another in the human TRPV4 channel. In particular, a single hydrophilic mutation in the lower pore can increase pore hydration and reduce the ion permeation free energy barrier by about half without affecting the bundle crossing. We believe that hydrophobic gating may play a key role in other bundle-crossing ion channels with hydrophobic inner pores. 
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Original research proposal (ORP) is an exam designed to test the ability of graduate students to identify significant scientific questions, to develop research proposals based on rationized and reasonable hypotheses, and more importantly to successfully defend the proposal. 
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CBI program (Chemistry-Biology Interface) is a highly competitive UMass-funded and NIH-funded fellowship, aiming at training trainees from different background to advance scientific research “at the interface of chemistry and biology”. 
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