Lego_vdM_wErase_Stack.jpg
 
 

Protein design

targeting function

 
 
 

Research

Most proteins function by first binding a ligand, such as another protein, peptide, or small molecule. The Polizzi laboratory aims to learn the rules of protein–ligand binding through the lens of de novo protein design. In de novo design, a protein’s structure and sequence are computed from first principles. This approach has seen much recent success for the creation of new protein shapes. However, the design of proteins that bind to specific ligands remains an outstanding challenge, due to the additional degrees of freedom introduced by a ligand and the subtle balance of energetics. In order to design functional proteins, we must first crack the “binding code.”

Our lab aims to tackle this challenge through a tight coupling of computation and experiment. We develop computational design methods that learn from protein structure and test these algorithms by making new ligand-binding proteins in the lab. We focus on designing proteins that bind to small molecules, as these are the most difficult targets for screening or immunization techniques. We build proteins that not only hone our design methods but also act as useful tools for biology, e.g., for metabolite sensing, proteome editing, and genetic-code expansion in mammalian cells. Ultimately, we hope that by cracking the ligand-binding code we open the door to the design of functional proteins not seen in nature.

 
 

Expanding the genetic code with protein design

Aminoacyl tRNA synthetases link amino acids with their cognate tRNAs and are thus critical players in the expansion of the genetic code. However, it has proven incredibly difficult to engineer synthetases to recognize polar, non-natural amino acids that mimic common post-translational modifications (PTMs) of proteins. The ability to precisely program PTMs and monitor their effects on cell fate in disease-relevant mammalian cells has been a longstanding goal. Toward this end, our group uses protein design methods to dramatically alter the substrate specificity of tRNA synthetases, focusing on challenging, polar PTM mimics.

 

Designing new protein-based tools

Biology can be monitored and manipulated by ligand-binding proteins. Until recently, however, the discovery of binding proteins depended on the serendipity of high-throughput experimental screening and animal inoculations. Now, our group has developed a computational method called COMBS that can generate protein sequences from scratch that are able to tightly and specifically bind to challenging targets. COMBS thus enables the rapid generation of proteins that may act as sensors, therapeutics, or delivery vehicles. We hope that by distilling the principles of ligand binding into a computational algorithm, we can make the design of ligand-binding proteins as routine as the design of primers for PCR, thereby eliminating the bottlenecks in monitoring and manipulating biology at the molecular level and, ultimately, paving the way for the design of de novo function.

 
neural network

Learning contextual signatures of molecular recognition

Our group is exploring new deep learning architectures to understand and predict ligand-binding cooperativity. We leverage custom-built databases to train and test models that learn molecular features that give rise to tight and specific binding of ligands.

 

Our Team

Our group is part of the Cancer Biology department at Dana-Farber Cancer Institute and the Biological Chemistry and Molecular Pharmacology department at Harvard Medical School.

 
 
 

Nick Polizzi, PhD
Assistant Professor

pronouns: he / him / his

Nick received his PhD in Biochemistry from Duke University, where he developed experimental and theoretical models to probe mechanisms of biological charge flow. He then moved to UCSF for his postdoctoral work, where he built new methods to design proteins from scratch that specifically bind to small molecules. At Harvard Medical School and Dana-Farber Cancer Institute, Nick aims to crack the “binding code” by designing ligand-binding proteins that can serve as useful tools for observing and manipulating biology.

NicholasF_Polizzi@DFCI.harvard.edu
Google Scholar
@nickpolizzi_
github

jody sitting on the side of a tall building

Jody Mou
Graduate Student

Jody graduated from Johns Hopkins University with a degree in biomedical engineering and is currently a PhD student in the Harvard-MIT HST program. During undergrad, she worked on molecular immunology at JHU and machine learning for protein engineering at Microsoft Research. Jody is working on de novo design of ligand-binding proteins using computational and deep learning approaches. She is interested in synthetic biology and research tool development. Outside of the lab, she enjoys making things and exploring new places.

jodymou@mit.edu

jerry wearing a backpack in the desert

Chun-Chen Jerry Yao
Graduate Student

Jerry is a graduate student in Harvard’s Molecules, Cells, and Organisms (MCO) program. He earned his BSc at MIT in Brain and Cognitive Science (BCS), where he optimized an in situ sequencing-by-synthesis method in Ed Boyden’s lab and Fei Chen’s lab; he also studied transcription-translation uncoupling in Bacillus subtilis in Gene-Wei Li’s lab. During his gap year before starting at Harvard, he served the Taiwanese army and then worked with Dan Tawfik at the Weizmann Institute to investigate the origin of peptides and the genetic code in the origin of life. For his PhD, he hopes to elucidate the principles of biomolecular evolution using protein design, evolutionary biology, and high-throughput experimental approaches. When he is not thinking about science, he enjoys cooking, hiking, backpacking, learning languages, and exploring the evolution of human artifacts.

cyao@g.harvard.edu

Jeffrey Chang
Graduate Student

Jeffrey is a graduate student in Harvard's physics department. As an undergraduate, he studied fluorescent protein photochemistry in Prof. Steve Boxer's lab at Stanford. Earlier in graduate school, he worked in statistical mechanics education with Prof. Steve Kivelson, analysis methods for single-molecule biophysics with Prof. Wesley Wong, and high-throughput assay development with Prof. Michael Desai. Currently, he wants to understand the basic principles of biomolecular specificity by designing peptide-binding proteins. In his spare time, he kickboxes, dances Lindy Hop, and plays in a jazz quartet called Mutual Beef.

jeffrey_chang@g.harvard.edu

Jing Sun
Graduate Student

Jing is a graduate student in the Biological and Biomedical Sciences (BBS) Program at Harvard. She graduated from Cornell University with a bachelor degree in Biological Sciences and in Statistical Science. During her undergrad, Jing studied viral proteins using X-ray crystallography at Cornell and worked on an ABC transporter using cryo-EM at Scripps Research. She enjoys skiing, traveling, eating, and playing with cats.

jingsun@g.harvard.edu

jesus in the mountains

Jesús Valdiviezo Mora, PhD
Postdoctoral Research Fellow

Jesús graduated from Tecnológico de Monterrey in Mexico with a BS in Chemistry. He moved to the United States on a Fulbright Fellowship and earned a PhD in Chemistry and a concurrent MS in Electrical and Computer Engineering at Duke University. At Duke, he worked with Prof. David Beratan using computational chemistry methods and electron transfer theory to characterize the electronic properties of bioinspired chemical systems. Prior to his arrival at the Polizzi lab, he was an NSF-funded Computing Innovation Fellow at the University of California, Berkeley, and worked on proton transfer dynamics in Prof. Teresa-Head Gordon’s lab. Jesús is interested in engineering novel enzymes with altered substrate selectivity for sensing and genetic code expansion. In his spare time, he enjoys traveling, hiking, and running.

JesusD_ValdiviezoMora@DFCI.harvard.edu

Ben Fry
Graduate Student

Ben graduated from Johns Hopkins University with his Bachelors in Biophysics and a minor in Computer Science. He is currently a PhD student in Harvard’s Biophysics Program. As an intern with the Rosetta Commons, he worked in Dr. Daniel Kulp’s lab at The Wistar Institute to develop a computational protocol that targets viral glycoprotein epitopes for immune recognition. He continued this work at Hopkins under Dr. Jeffrey Gray. He is broadly interested in developing new computational techniques for protein design with the hope that they can be used to create the next generation of protein-based therapeutics. Outside of the lab, Ben enjoys exploring the city, hiking, cooking, and playing guitar.

bfry@g.harvard.edu

Masy Domecillo
Research Technician

Masy graduated from Andrews University, where she received her BSc in Biology. In the Lyons lab at Andrews, she examined how the prodomain region of a carboxypeptidase affects its function. She also worked in the Fedulov lab at Brown University to determine the effects of cardiac ischemia on the methylome. Outside of the lab, Masy enjoys traveling, film photography, and pestering her cat.

Masy_Domecillo@DFCI.harvard.edu

Anna Lian
Undergraduate Student

pronouns: she / her / hers

Anna is an undergraduate student at MIT pursuing a major in biological engineering. She is interested in exploring ligand-binding protein design and its potential for therapeutic applications, and is excited by the intersection between computational, chemical, and biological research. Outside of the Polizzi Lab, Anna loves making art, exploring with friends, and taking walks with her dog Mango.

annalian@mit.edu

amina menhour

Amina Menhour
Master’s Student

Amina graduated from CPE LYON, where she received her BSc in Mathematics, Physics, and Chemistry. She then specialized in medicinal chemistry and process engineering, and worked in Zurich in the synthesis of potential hits for targeting CAIX protein in renal cell carcinoma, and the construction of DNA-Encoded Chemical Libraries. She then moved to EPFL, Ecole Polytechnique Fédérale de Lausanne, for her MSc to specialize in Computational Chemistry and Machine Learning methods. She worked in the lab of Patrick Barth on the analysis of the molecular mechanics of active GPCRs and their allosteric pathways. In the Polizzi Lab, Amina is doing her master thesis on computing protein/fragment interaction energies on large datasets using semi-empirical and DFT methods, and training deep neural networks. Outside of the lab, Amina enjoys traveling, socializing, going out with friends, and exploring the city.

Amina_Menhour@DFCI.harvard.edu

Roksana Azad
Postdoctoral Research Fellow

Roksana grew up in Bangladesh and later immigrated to the United States, where she completed her B.S. with academic honors in Chemistry and Biochemistry from York College. She received her Ph.D. in Biochemistry and Molecular Biophysics from the CUNY Advanced Science Research Center working in Prof. Kevin Gardner's lab. During her Ph.D., Roksana studied the superfamily of PAS/LOV sensory domains and their regulatory control of Ser/Thr kinases in plants and humans. Her thesis research characterized the structure and function of the allosteric regulation of PAS to control the kinase function using integrated techniques including NMR (high-pressure, 2D/3D), HDX-MS, cryo-EM, and X-ray. In her free time, Roksana is passionate about volunteering in STEM outreach, and she enjoys cooking, watching soccer and cricket, outdoor activities, and keeping up with recent scientific discoveries.

Roksana_Azad@DFCI.harvard.edu

Jio Jeong
Rotating Graduate Student

Jio is a graduate student in the Chemistry and Chemical Biology (CCB) department at Harvard University. She graduated from University of Pennsylvania with a bachelor’s degree, majoring in chemistry and computer science. During undergrad, she worked in Prof. Jeffery Saven’s lab, and studied self-assembling peptide “bundlemers” that can be linked together into customizable polymers with click chemistry. Outside of the lab, she enjoys exploring the city and discovering new music.

jiojeong@g.harvard.edu

Kevin Tan
Undergraduate Student

pronouns: he / him / his

Kevin is an undergraduate at Harvard studying computer science and molecular & cellular biology. He is interested in how machine learning can be used to facilitate protein structure design and in developing biotechnology applications. You can find him in his spare time cafe hopping in Boston, reading The Verge, and learning new choreography.

kevintan@college.harvard.edu

kekui portrait

Keku'i Ledward
Executive Support Specialist

Keku’i has been with the Department of Cancer Biology since 2013. When not working, she enjoys learning about Pokémon with her eldest son and her partner, making up songs with both her kiddos and playing her ukulele. Got a question? Reach out to Keku’i. If she doesn’t have the answer, she’ll figure out who does.

Kekui_Ledward@DFCI.harvard.edu

 

Lab Alumni

Varun Ullanat Current Position: Master’s Student, Biomedical Informatics, HMS

James Davey Current Position: Assistant Professor, Dalhousie University, Nova Scotia, Canada

Bryan Banuelos Jara Current Position: Balskus Lab, Harvard

Ryan Acbay Current Position: Graduate Student, MCO program, Harvard

Tessa Haining Current Position: Rhodes Scholar, Oxford UK

Marco Hansel Current position: Harvard undergraduate

Gabe Au Current position: Johns Hopkins undergraduate

 

publications

 
 

A defined structural unit enables de novo design of small-molecule-binding proteins.

N. F. Polizzi, W. F. DeGrado. Science. 369, 1227–1233 (2020).

PubMed ID: 32883865
Github Repos: combs

Perspective in Science by Dr. Anna Peacock

Research Highlight: Nature Methods

News Coverage: Chemistry World, Phys.org

Deposited Structures: 6w70, 6w6x, 6x8n


De novo design of a hyperstable non-natural protein-ligand complex with sub-Å accuracy.

N. F. Polizzi, Y. Wu, T. Lemmin, A. M. Maxwell, S.-Q. Zhang, J. Rawson, D. N. Beratan, M. J. Therien, W. F. DeGrado. Nature Chemistry. 9, 1157–1164 (2017).

PubMed ID: 29168496

News Coverage: Duke Research News

Cover Image

Deposited Structures: 5tgy, 5tgw


Allosteric cooperation in a de novo-designed two-domain protein.

F. Pirro, N. Schmidt, J. Lincoff, Z. X. Widel, N. F. Polizzi, L. Liu, M. J. Therien, M. Grabe, M. Chino, A. Lombardi, W. F. DeGrado. Proc. Natl. Acad. Sci. U. S. A. 117, 33246–33253 (2020).

PubMed ID: 33318174

Deposited Structures: 7jh6

 

Lab news

 

Aug 13th, 2022

Jody and Jerry officially join the lab! We are thrilled to continue our work together on some of the most pressing issues in ligand-binding protein design!


May 8th, 2022

Jody was awarded the T.S. Lin Fellowship at MIT, which will fund her graduate studies for a year! Congrats, Jody!


May 3rd, 2022

Welcome to Jerry and Jody, who are starting their rotations in the group! Jerry joins from Harvard’s MCO program, and Jody from the joint Harvard-MIT HST program.


 

Doors open!

The Polizzi Lab opened its doors on May 2, 2022. Our lab is located on the 4th floor of the Longwood Center (LC), one of the newest buildings in the Longwood / Harvard Medical School area. The LC has incredible core facilities and research space for pursuing our protein design work. We’re situated among other Cancer Biology faculty, which makes for easy collaboration!


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Join the team

We consider applications on a rolling basis. If you are interested in joining a growing, collaborative team working at the forefront of protein design, please email Nick your CV and a statement explaining your goals and interests.

 
 

Postdocs

We are always looking for highly motivated postdocs with computational and/or experimental skills and a passion for protein structure/function/design. We have lots of exciting projects involving protein design, high-throughput experiments, and structure determination.


Graduate students

We’re recruiting graduate students who are accepted into Harvard or Harvard/MIT PhD programs! Please reach out to Nick directly via email with a description of your interests. (MIT graduate students who are not in a joint program can be co-advised with an MIT faculty.) Prospective graduate students are also encouraged to reach out, although in order to join the group they must first be admitted into a PhD program.


Research technician

We are looking for a research technician to join our team! This is an entry-level position that would be perfect for someone coming out of undergrad with some laboratory experience (e.g., purifying proteins) who wants to get more hands-on research experience in a cutting-edge protein design lab before going on to graduate school or biotech/industry. As a research technician, you will get lots of hands on experience with protein expression, purification, structure determination, and making biophysical measurements. You will also be exposed to the computational side of protein design (although this position is primarily for an experimentalist who will work in the “wet lab”). If interested, reach out to Nick via email and/or apply for the position via the link below!

Contact Us

 
 

Email

Executive Support:
Keku’i Ledward: Kekui_Ledward@DFCI.harvard.edu

Principal Investigator:
Nick Polizzi: NicholasF_Polizzi@DFCI.harvard.edu

Location

360 Longwood Ave
Longwood Center (LC)
Boston, MA 02215

Office: LC-4312

Lab: LC-4302