I want to express my deepest gratitude to Prof. Jianhan for his guidance and supervision during my PhD program. Thanks to him, I had many valuable opportunities to work in the field of computational biophysics, including molecular mechanism studies of ion channel functions, coarse-grained simulations for protein domain interactions as well as Al-driven ensemble generative modeling. I could not have done any of those without his tremendous and unconditional supports. I would like to also thank many other people, my dissertation committee members, all my lab members, my dear friends and family members for their supports in various aspects.

Finishing the PhD study was indeed a highly rewarding journey where I gained scientific skills, mental strength, and friendships.

The annual ResearchFest in the Chemistry department is almost the biggest event of the whole year. In the ResearchFest event, graduate students from the department will participate in poster presentations or luckily get selected as the key presentators to present our fascinating research. Judges, usually our dear faculty members, will grade the quality of the presentation and science for all presentations, based on which students will win awards. Super fun! You can get more information from: UMass Chemistry ResearchFest.

In the event this year, I was selected as one of the key presentator to give a presentation to the whole department, including new coming graduate students. I focused the talk on the gating mechanisms of ion channels.

Jian in the presentation

Jian was awarded the 2nd place for the presentation

I also participated in the post presentation section as one of the many audience. Always nice to hear people talking about exciting science projects.

The 2021-batch graduate students

I really want to thank my professor Jianhan Chen who always gives me great suggestions and provides me with many opportunities; my mentor Mahdieh Yazdani (during merck internship) who help me with my researchfest presentation, and all my labmates who have always been supportive.

Transient receptor potential (TRP) channels are a large and diverse family of transmembrane ion channels that are widely expressed, have important physiological roles, and are associated with many human diseases. These proteins are actively pursued as promising drug targets, benefitting greatly from advances in structural and mechanistic studies of TRP channels. At the same time, the complex, polymodal activation and regulation of TRP channels have presented formidable challenges. A particular focus is on the current understanding of the molecular mechanisms of TRP channel activation and regulation, where many fundamental questions remain unanswered. We believe that a deeper understanding of the functional mechanisms of TRP channels will be critical and likely transformative toward developing successful therapeutic strategies targeting these exciting proteins. This endeavor will require concerted efforts from computation, structural biology, medicinal chemistry, electrophysiology, pharmacology, drug safety and clinical studies.

In this work, we first summarized all kinds of TRP-related genetic diseases (channelopathies) to emphasize the necessity of developping TRP-targeting drugs for therapeutics.

Then, we went through all six TRP subfamilies to summarize all reported ligand-binding pockets from the currectly available structural data from the PDB database. Below are the figures summarizing TRPM and TRPC binding pockets. Detailed annotations including activation or inhibition are added in the figures.

Ligand-binding pocket in TRPMs

Ligand-binding pocket in TRPCs

Many thanks to Prof. Jianhan Chen, Mahdieh Yazdani, Aron Korsunsky for their support during the whole manuscript preparation and submission process.

In this work, we performed atomistic molecular dynamics (MD) simulations in explicit solvent to investigate the hydration property of TRPV4 pore in the closed state, and further determined the free energy profile of K+ permeation to identify the location of the actual gate. To dissect the contributions of hydrophobic gating and bundle crossing to channel gating, we analyzed the pore hydration and K+ permeation-free energy properties of a hydrophilic and non-pore-facing mutation I715N near the bundle crossing, which was experimentally found to increase the resting channel activity of TRPV4. Our results strongly support that both bundle-crossing and hydrophobic gating indeed contribute to TRPV4 inactivation. Given the prevalence of hydrophobic inner pores in ion channels, the current study suggests that hydrophobic gating likely plays a more general role than previously thought, regardless of the presence of bundle crossing in the deactivated channel.

The above figure shows that I715N has a significantly smaller barrier compared with the WT.

Many thanks to my supervisor, Jianhan, for his support during the whole manuscript preparation and submission process.

In my proposal, I want to make novel photoenzymes for unnatural transformation. Creating novel enzymes for unnatural transformations is extremely beneficial for industry production of fine organic compound. Creating novel photoenyzmes (the regime of Photo-biocatalysis) can potential combine the advantages of biocatalysis such as efficiency, stereoseletivity and sustainability, and photocatalysis for the highly reactive species and mechanistic versatility.
I propose to use cofactor substitution to replace the natural cofactor in the cofactor-dependent enzymes to gain new-to-nature and controllable reactivities (see the picture above).

Here, I want to say thanks to my supervisor, committee members and lab mates. My lab mates helped me practiced many times for the presentation and gave me lots of useful questions and suggestions. Jianhan and all my committee members were super helpful and gave me lots of constructive suggestions and questions during the defense.

What I did so far as a CBI trainee

1. Drug design course
   • Understand drug development process, including drug discovery, screening, optimization and clinical trials;
   • Computational aided drug discovery and Structural-based drug design;
   • Macromolecular drug development, such as antibody, DNA and RNA.
2. CBI chalk talk
   • CBI chalk talk is a course that is monthly held to gather CBI community to disscuss cutting edge topics.
3. attend workshops
   • I attended a OPT workshop “Crafting Slides for Engaging Presentations” (Nov 16th). I also made my own logo and PPT template.
4. CBI traineeship talk
   • As a CBI trainee, I was requested to give a talk to both chemistry and biology students
   • The talk topic: Hydrophobic gating in bundle-crossing ion channels: a case study of TRPV4”
5. Future plan

The BPS 2022 66-th annual meeting was held in 19th Feb 2022 at San Francisco, California.

During this meeting, I presented a post about the new findings of TMEM16F, including:

1. A conductive/open state of mTMEM16F induced by inner gate charged mutations was identified during atomistic simulations. (see TMEM16F)
2. The predicted state is permeable to ions and lipids, which further reveals the ion and lipid pathways (as well as underlying mechanisms) of this protein.

This was a fun trip! All Chen lab members gathered and enjoyed the meeting. We even had a fascinating road trip to get back to MA.

The frist “reunion” of the Chen lab after each of us arrived at San Francisco, CA.

Hiking to the beach (From left to right: Jian, Erik, Xiping & Sam)

Visiting the Chinatown in San Francisco

Visiting the Chinatown in San Francisco (in the front gate)
Everything under the sky belongs to all – 天下为公

Chen lab members at the peak of the Twin Peaks (It’s freezing…)

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.