About

We are a multidisciplinary group of scientists in the Departments of Chemistry and Microbiology & Immunology and also affiliated with the Sarafan ChEM-H Institute. We are driven to decipher the molecular bases of complex biological phenomena. We seek to elucidate and exploit the synthesis and trafficking of metabolites essential for bacteria proliferation and pathogenesis, and to develop broadly applicable strategies for the post-translational modulation of intractable disease-relevant proteins.

Research topics

• Chemistry
• Biology
• Biochemistry
• Computational biology
• Cell biology

Selected publications

• Raw flow cytometry data for "Engineering Cell-Specific Protein Delivery Vehicles for Erythroid Lineage Cells"

  2026-03-06

  dataset1st authorCorresponding
  PublisherDOI

• A lipid compendium of a metabolically compromised bacterium provides insights into lipid acquisition, biosynthesis, and metabolism

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-23

  articleOpen accessSenior author

  The Lyme disease agent Borrelia burgdorferi belongs to a class of metabolically compromised bacteria that cannot survive without host-derived lipids. Survival of the agent in tick and vertebrate hosts requires substantial nutrient acquisition and potential cell envelope remodeling. While prior studies identified cholesterol, cholesterol glycolipids, and phosphatidylcholines as membrane lipids in B. burgdorferi, the identity of many other membrane lipids, their origin, and their physiological relevance remain unknown. Here, we used a suite of untargeted and targeted high-resolution mass spectrometry methods to reveal a complex lipid profile of the pathogen and to identify the origin of its lipids. The analysis detected more than 500 lipids in B. burgdorferi, the majority of which are sourced from the environment. However, the bacterium selectively accumulates certain lipids while excluding others, suggesting discriminatory uptake. These include cholesteryl esters and triglycerides that are organized in foci within the pathogen. Intriguingly, the pathogen also synthesizes predominantly eukaryotic lipids such as the lysosomal bis(monoacylglycerol)phosphate and the plant glycolipid sulfoquinovosyl diacylglycerol (SQDG). The biosynthesis of the latter is carried out by enzymes that exhibit structural homology to plant oxidoreductases and galactosyltransferases, yet their closest orthologs are found in bacteria. This hints that the capability of SQDG synthesis is more widespread in spirochaetes and other bacteria. Together, the comprehensive lipid profiling we report here uncovers novel aspects of the physiology of the metabolically challenged B. burgdorferi and highlights lipid acquisition and synthesis pathways as potentially critical for pathogen survival.

  PublisherDOI

• A Machine Learning Model for the Proteome-Wide Prediction of Lipid-Interacting Proteins

  Journal of Chemical Information and Modeling · 2025-09-04 · 1 citations

  articleOpen accessSenior authorCorresponding

  Lipids are essential metabolites that play critical roles in multiple cellular pathways. Like many primary metabolites, mutations that disrupt lipid synthesis can be lethal. Proteins involved in lipid synthesis, trafficking, and modification, are targets for therapeutic intervention in infectious disease and metabolic disorders. The ability to rapidly detect these proteins can accelerate their evaluation as targets for deranged lipid pathologies. However, it remains challenging to identify lipid binding motifs in proteins because the rules that govern protein engagement with specific lipids are poorly understood. As such, new bioinformatic tools that reveal conserved features in lipid binding proteins are necessary. Here, we present Structure-based Lipid-interacting Pocket Predictor (SLiPP), an algorithm that leverages machine learning to detect protein cavities capable of binding to lipids in protein structures. SLiPP uses a Random Forest classifier and operates at scale to predict lipid binding pockets with an accuracy of 96.8% and an F1 score of 86.9% when testing against a set of 8,380 pockets embedded within proteins. Our analyses revealed that the algorithm relies on hydrophobicity-related features to distinguish lipid binding pockets from those that bind to other ligands. SLiPP is fast and does not require substantial computational resources. Use of the algorithm to detect lipid binding proteins in various proteomes produced hits annotated or verified as bona fide lipid binding proteins. Additionally, SLiPP identified many new putative lipid binders in well studied proteomes. Because of its ability to identify novel lipid binding proteins, SLiPP can spur the discovery of new and “targetable” lipid-sensitive pathways.

  PublisherOA PDFDOI

• Engineering Cell-Specific Protein Delivery Vehicles for Erythroid Lineage Cells

  ACS Bio & Med Chem Au · 2025-02-27 · 1 citations

  articleOpen accessSenior authorCorresponding

  Biologics such as proteins, peptides, and oligonucleotides are powerful ligands to modulate challenging drug targets that lack readily accessible and “ligandable” pockets. However, the limited membrane permeance of biologics severely restricts their intracellular applications. Moreover, different cell types may exhibit varying levels of impermeability, and some delivery vehicles might be more sensitive to this variance. Erythroid lineage cells are especially challenging to deliver cargo to because of their unique cytoskeleton and the absence of endocytosis in mature erythrocytes. We recently employed a cell permeant miniature protein to deliver bioPROTACs to human umbilical cord blood derived erythroid progenitor cells (HUDEP-2) and primary hematopoietic stem (CD34+) cells (Shen et al., ACS Cent. Sci. 2022, 8, 1695−1703). While successful, the low efficiency of delivery and lack of cell-type specificity limit use of bioPROTACs in vivo. In this work, we thoroughly evaluated the performance of various recently reported cell penetrating peptides (CPPs), CPP additives, bacterial toxins, and contractile injection systems for their ability to deliver cargo to erythroid precursor cells. We also explored how targeting receptors enriched on the erythroid cell surface might improve the efficiencies and specificities of these delivery vehicles. Our results reveal that certain vehicles exhibit improved efficiencies when directed to cell surface receptors while others do not benefit from this targeting strategy. Together, these findings advance our understanding of protein delivery to challenging cell types and illustrate some of the intricacies of cell-surface receptor targeting.

  PublisherOA PDFDOI

• Investigating the Effect of Membrane Composition on the Selective Ammonium Transport of E. coli AmtB Membrane Proteins

  ChemRxiv · 2025-04-07

  preprintOpen access

  Selective membrane separation processes can recover ammonia from wastewaters and advance a circular nutrient economy. E. coli AmtB (EcAmtB) is a well-characterized and ammonium-selective membrane protein that could be embedded into synthetic membranes. However, the effects of phospholipids present in E. coli membranes, namely 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG), on EcAmtB folding and function remain undetermined. Solid-supported membrane-based electrophysiology (SSME) was conducted to observe ammonium migration through EcAmtB proteoliposomes containing varying compositions of phospholipids POPE, POPG, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphate (POPA). In contrast to previous reports highlighting the singular importance of POPG for ammonia transport, this study found that proteoliposomes containing POPE adhered to SSME sensors exhibited the highest total ammonium permeability (2498 pA of total sensor current or 15.59 billion cations per second). A crucial phospholipid head group bonding site may be the E70 location, a glutamate at the junction of two protein subunits. Understanding how phospholipid-protein bonding determines transport performance can aid in developing similar protein-synthetic membrane bonding structures for industrial selective recovery processes.

  PublisherOA PDFDOI

• Identifying Opportunity Targets in Gram-Negative Pathogens for Infectious Disease Mitigation

  ACS Central Science · 2025-01-03 · 2 citations

  reviewOpen accessSenior authorCorresponding

  Antimicrobial drug resistance (AMR) is a pressing global human health challenge. Humans face one of their grandest challenges as climate change expands the habitat of vectors that bear human pathogens, incidences of nosocomial infections rise, and new antibiotics discovery lags. AMR is a multifaceted problem that requires a multidisciplinary and an "all-hands-on-deck" approach. As chemical microbiologists, we are well positioned to understand the complexities of AMR while seeing opportunities for tackling the challenge. In this Outlook, we focus on vulnerabilities of human pathogens and posit that they represent "opportunity targets" for which few modulatory ligands exist. We center our attention on proteins in Gram-negative organisms, which are recalcitrant to many antibiotics because of their external membrane barrier. Our hope is to highlight such targets and explore their potential as "druggable" proteins for infectious disease mitigation. We posit that success in this endeavor will introduce new classes of antibiotics that might alleviate some of the current pressing AMR concerns.

  PublisherDOI

• Investigating the Effect of Membrane Composition on the Selective Ammonium Transport of <i>Escherichia coli</i> AmtB Membrane Proteins

  ACS Applied Engineering Materials · 2025-05-29 · 1 citations

  article

  Selective membrane separation processes can recover ammonia from wastewater and advance a circular nutrient economy. Escherichia coli AmtB (EcAmtB) is a well-characterized, ammonium-selective membrane protein that could be embedded into synthetic membranes. However, the effects of phospholipids present in E. coli membranes, namely, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG), on EcAmtB folding and function remain undetermined. Solid-supported membrane-based electrophysiology (SSME) was conducted to observe ammonium migration through EcAmtB proteoliposomes containing varying compositions of phospholipids POPE, POPG, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphate (POPA). In contrast to previous literature support in favor of POPG, this study found that proteoliposomes containing POPE adhered to SSME sensors exhibited the highest total ammonium permeability (2498 pA of total sensor current or 15.59 billion cations per second). A crucial phospholipid headgroup bonding site may be the E70 location, a glutamate at the junction of two protein subunits. Understanding how phospholipid–protein bonding determines the transport performance will aid in developing similar protein–synthetic membrane bonding structures for industrial selective recovery processes.

  PublisherDOI

• Protein-Based Degraders: From Chemical Biology Tools to Neo-Therapeutics

  Chemical Reviews · 2025-01-17 · 19 citations

  reviewOpen accessSenior authorCorresponding

  The nascent field of targeted protein degradation (TPD) could revolutionize biomedicine due to the ability of degrader molecules to selectively modulate disease-relevant proteins. A key limitation to the broad application of TPD is its dependence on small-molecule ligands to target proteins of interest. This leaves unstructured proteins or those lacking defined cavities for small-molecule binding out of the scope of many TPD technologies. The use of proteins, peptides, and nucleic acids (otherwise known as "biologics") as the protein-targeting moieties in degraders addresses this limitation. In the following sections, we provide a comprehensive and critical review of studies that have used proteins and peptides to mediate the degradation and hence the functional control of otherwise challenging disease-relevant protein targets. We describe existing platforms for protein/peptide-based ligand identification and the drug delivery systems that might be exploited for the delivery of biologic-based degraders. Throughout the Review, we underscore the successes, challenges, and opportunities of using protein-based degraders as chemical biology tools to spur discoveries, elucidate mechanisms, and act as a new therapeutic modality.

  PublisherOA PDFDOI

• Author Response: Novel sterol binding domains in bacteria

  2024-02-08

  peer-reviewOpen access1st authorCorresponding
  PublisherDOI

• Unveiling of a messenger: Gut microbes make a neuroactive signal

  Cell · 2024-06-01 · 3 citations

  articleOpen accessSenior authorCorresponding
  PublisherOA PDFDOI

Recent grants

• Deciphering the molecular mechanisms of sterol lipid trafficking in bacteria

  NIH · $1.5M · 2023–2028

• Copper Acquisition by Methanotrophs.

  NIH · $164k · 2014–2017

Frequent coauthors

• Liting Zhai

  Hunan University of Science and Engineering

  84 shared

• Jonathan Chiu‐Chun Chou

  Stanford University

  84 shared

• Hannah Oo

  Stanford Synchrotron Radiation Lightsource

  79 shared

• Clyde A. Smith

  Stanford University

  78 shared

• Amber C. Bonds

  National Institute of Neurological Disorders and Stroke

  77 shared

• Paula V. Welander

  Stanford University

  77 shared

• Carsten Krebs

  Pennsylvania State University

  47 shared

• Wei Jiang

  39 shared

Labs

• Laura M.K. Dassama LabPI

Education

• Doctor of Philosophy, Biochemistry and Molecular Biology

  Pennsylvania State University

  2013