Publications

[14] Chen, Z., Elowitz, M.B., (2021). Programmable protein circuit design. Cell 184, 2284–2301.

• In cells, proteins act collectively to sense, transmit, process signals, and generate dynamic control over cellular behaviors. How can we design protein-level circuits by programming proteins and their interactions? In this review, we attempt to establish design principles, highlight past work, and suggest future directions in the new field of protein circuit design. PDF

[13] Yu, M., Zhao, Z., Chen, Z., Le, S., Yan, J., (2020). Modulating mechanical stability of heterodimerization between engineered orthogonal helical domains. Nat. Commun. 11, 4476.

• One of my favorite features of the designed heterodimers in Ref [5] is that they are modular and programmable. Using a single molecule technique called magnetic tweezers, Jie Yan and his lab showed that the mechanical stability of these heterodimers can be modularly tuned in a wide range simply by changing the stretching points and number of helices. PDF

[12] Chen, Z., Kibler, R.D., Hunt, A., Busch, F., Pearl, J., Jia, M., VanAernum, Z.L., Wicky, B.I.M., Dods, G., Liao, H., Wilken, M.S., Ciarlo, C., Green, S., El-Samad, H., Stamatoyannopoulos, J., Wysocki, V.H., Jewett, M.C., Boyken, S.E., Baker, D., (2020). De novo design of protein logic gates. Science 368, 7884.

• Synthetic biology has traditionally focused on building nucleic acid-based circuits, thanks to the ease of programming DNA or RNA molecules. Now that we have proteins that behave in a similar way (Refs 2, 5, 10), wouldn’t it be fun to build protein-based circuits? Here we demonstrate a way to create logic gates from scratch, using de novo designed heterodimers. These building blocks offer not only programmability, but also robustness and transferability: they work as purified proteins, in cell-free extracts, yeasts, and T cells. PDF, Physics Today, Nature Methods, GEN

Cover art by Demin Liu, MolGraphics

[11] VanAernum, Z.L., Busch, F., Jones, B.J., Jia, M., Chen, Z., Boyken, S.E., Sahasrabuddhe, A., Baker, D., Wysocki, V.H. (2020). Rapid online buffer exchange for screening of proteins, protein complexes and cell lysates by native mass spectrometry. Nature Protocols

• Native mass spectrometry is a technique that reveals the mass of protein complexes without destroying the non-covalent bonds that hold them together. Our collaboration with the Wysocki lab at OSU has been extremely fruitful, and here is a detailed protocol for doing high throughput native mass spectrometry, a core technique we used in Ref [5]. PDF

[10] Chen, Z. (2019). Creating the protein version of DNA base pairing. Science 366, 965-965.

• This Science & SciLifeLab Prize essay summarizes my PhD work. It describes a way to achieve DNA-like programmable specificity in proteins via computational design, which extends to the creation of a large set of orthogonal protein heterodimers, protein-based logic gates that operate in living cells, and lego-like proteins that self-assemble into two-dimensional materials. PDF

[9] Langan, R.A., Boyken, S.E., Ng, A.H., Samson, J.A., Dods, G., Westbrook, A.M., Nguyen, T.H., Lajoie, M.J., Chen, Z., Berger, S., Mulligan, V.K., Dueber, J.E., Novak, W.R.P., El-Samad, H., Baker, D., (2019). De novo design of bioactive protein switches. Nature 572, 205–210.

• Here is a protein that is able to change conformation, designed based on a homotrimer from Ref [2]. PDF

[8] Cao, L., Yu, B., Kong, D., Cong, Q., Yu, T., Chen, Z., Hu, Z., Chang, H., Zhong, J., Baker, D., He, Y., (2019). Functional expression and characterization of the envelope glycoprotein E1E2 heterodimer of hepatitis C virus. PLoS Pathog. 15, e1007759.

• Speaking of practical applications of my designed heterodimers, turns out they can aid the determination of cryo-EM structures! PDF

[7] Boyken, S.E., Benhaim, M.A., Busch, F., Jia, M., Bick, M.J., Choi, H., Klima, J.C., Chen, Z., Walkey, C., Mileant, A., Sahasrabuddhe, A., Wei, K.Y., Hodge, E.A., Byron, S., Quijano-Rubio, A., Sankaran, B., King, N.P., Lippincott-Schwartz, J., Wysocki, V.H., Lee, K.K., Baker, D., (2019). De novo design of tunable, pH-driven conformational changes. Science 364, 658-664.

• Another work using the protein equivalent of Watson-Crick base pairing, this time adding a spice of dynamics into such designs – proteins that disassemble at low pH and reassemble at high pH. PDF

[6] Chen, Z., Johnson, M.C., Chen, J., Bick, M.J., Boyken, S.E., Lin, B., De Yoreo, J.J., Kollman, J.M., Baker, D., DiMaio, F., (2019). Self-assembling 2D arrays with de novo protein building blocks. J. Am. Chem. Soc. 141, 8891-8895.

• Back in 2011 when I was an undergrad working on DNA origami I wondered when we could build “protein origamis”. Eight years later I designed and verified such tiny structures! PDF

Cover art by Demin Liu, MolGraphics

[5] Chen, Z., Boyken, S.E., Jia, M., Busch, F., Flores-Solis, D., Bick, M.J., Lu, P., Van Aernum, Z.L., Sahasrabuddhe, A., Langan, R.A., Bermeo, S., Brunette, T., Mulligan, V.K., Carter, L.P., DiMaio, F., Sgourakis, N.G., Wysocki, V.H., Baker, D. (2019). Programmable design of orthogonal protein heterodimers. Nature 565, 106-111.

• We created a large set of de novo protein heterodimers, which bind each other specifically via the protein version of Watson-Crick base pairing. This set of orthogonal heterodimers should enable a variety of synthetic biology applications (protein logic gates, bio-orthogonal circuits, etc.) PDF, The Economist, Phys.org

Cover art by Demin Liu, MolGraphics

[4] Lu, P., Min, D., DiMaio, F., Wei, K.Y., Vahey, M.D., Boyken, S.E., Chen, Z., Fallas, J.A., Ueda, G., Sheffler, W., Mulligan, V.K., Xu, W., Bowie, J.U., Baker, D. (2018). Accurate computational design of multipass transmembrane proteins. Science 359, 1042-1046.

• Membrane proteins have been notoriously hard to work with, but turns out our soluble helical bundles could be re-engineered into membrane proteins. What is next, de novo designed membrane channels? PDF

[3] Thubagere, A.J., Li, W., Johnson, R.F., Chen, Z., Doroudi, S., Lee, Y.L., Izatt, G., Wittman, S., Srinivas, N., Woods, D., Winfree, E., Qian, L. (2017). A cargo-sorting DNA robot. Science 357, eaan6558.

• During my undergrad studies I was part of a team at Caltech that built DNA robots. We engineered nanoscopic DNA robots that deliver cargoes pretty much like FedEx, but with much smaller couriers. PDF, Los Angeles Times

[2] Boyken, S.E., Chen, Z., Groves, B., Langan, R.A., Oberdorfer, G., Ford, A., Gilmore, J.M., Xu, C., DiMaio, F., Pereira, J.H., Sankaran, B., Seelig, G., Zwart, P.H., Baker, D. (2016). De novo design of protein homo-oligomers with modular hydrogen-bond network-mediated specificity. Science 352, 680-687.

• DNA uses Watson-Crick base pairing to confer binding specificity (A binds T, and C binds G). What if we could create similar pairing codes in proteins from scratch? PDF, Science Perspective, Geekwire

[1] Chen, Z., Tan, J.Y., Wen, Y., Niu, S., Wong, S.-M. (2012). A game-theoretic model of interactions between Hibiscus latent Singapore virus and tobacco mosaic virus. PLoS One 7, e37007.

• My first paper! Here we used game theory to predict the competition outcome between two plant viruses. PDF