2024-25 Seminars

• Abstract: Photoenzymes are a new class of photoredox catalysts that are repurposed from natural enzymes that do not rely on light to function. The understanding and design of photophysical and photochemical processes in macromolecules, such as those in photoenzymes, are critical in developing molecular systems for solar to chemical energy conversion, new chemical synthesis strategies for pharmaceuticals, and light-responsive materials. However, accurate first-principles simulations of the electronic structure of macromolecules are usually computationally expensive, especially those that involve strong correlation. In this talk, I will discuss our computational strategies, including data-driven methods and quantum computing, to circumvent this issue. I will also discuss our recent work on combining first-principles simulations and data-driven methods to elucidate design and discovery strategies for photoenzymes and to inform experimental studies.
  
  
  
• Bio: Dr. Sijia Dong is an assistant professor in the Department of Chemistry and Chemical Biology at Northeastern University, with affiliations in the Department of Physics and the Department of Chemical Engineering. Sijia is passionate about accelerating science using computation and automation. She received her PhD in Chemistry from California Institute of Technology in 2017, advised by Prof. William A. Goddard III. She carried out her postdoctoral research at the University of Minnesota with Prof. Donald G. Truhlar and Prof. Laura Gagliardi, and then at Argonne National Laboratory with Prof. Giulia Galli. Research in the Dong Lab focuses on developing and applying physics-based and data-driven computational methods on both classical and quantum computers to accelerate chemical discoveries, especially on leveraging microenvironment tuning to design new chemistry and physics. Sijia has been selected a Scialog Fellow for Automating Chemical Laboratories by Research Corporation for Science Advancement and has won the Northeastern University College of Science Excellence in Mentorship Award. Sijia is also a Chair of the Early Career Board of the Journal of Chemical Theory and Computation. Research in the Dong Lab has been supported by DOE, NSF, NIH, and Mathworks.

• Abstract: "Have you ever wondered how viruses operate? How do they know which cells to infect? How do they “take over” a cell to cause it to make more viral particles? And why does this lead to disease and sometimes death? This presentation aims to demystify the inner workings of viruses, on a biophysical and biochemical level. Sharing work from my research lab, I will focus on the initial stages of infection using the Sendai virus which serves as an important model of viral infection. Although lesser-known, Sendai virus belongs to the same family as familiar respiratory viruses like mumps, measles, and parainfluenza viruses. The first steps of infection involve binding to host cells and merging with their membranes, a process known as membrane fusion. These steps are carried out by membrane proteins on the viral surface and are important targets for antiviral drug and vaccine development. While the key players in these processes have been identified, biophysical understanding of the mechanism has been challenging because these steps involve many molecules and a range of timescales. This presentation will highlight our investigations into receptor binding and membrane fusion of Sendai virus using a single-virus approach that involves microfluidic-based fluorescence measurements of individual viruses. I will discuss the biophysical insights that these investigations have yielded into the molecular mechanisms of binding and fusion for Sendai virus.."
  
  
• Bio: 

  Bob Rawle is an Assistant Professor of Chemistry at Williams College since 2018. He is a biophysical chemist by training and is interested in the biophysics of viral infection and lipid membranes. He received his BA in chemistry at Pomona College in 2008, where he worked in the laboratories of Profs. Cynthia Selassie and Malkiat Johal to develop bio-analytical methods to study DNA damage. He earned his PhD in chemistry (emphasis: biophysical chemistry) at Stanford University in 2014, working with Prof. Steve Boxer to study the membrane biophysics of vesicle fusion. He then did postdoctoral work at the University of Virginia Medical School with Prof. Peter Kasson studying the biophysics of influenza virus and Zika virus membrane fusion. Afterward, he had a short (but awesome) stint as a stay-at-home dad. 

  Bob loves teaching both in and out of the classroom. At Williams, Bob teaches classes in introductory chemistry, biochemistry, and biophysical chemistry. Outside of work, Bob regularly transforms into a terrifying ice dragon named Ice Fang and chases his three kids around the house. He enjoys swimming, cooking, and being outdoors.

• Abstract: "Phosphoglycosyl transferases (PGTs) are membrane-associated enzymes that initiate the biosynthesis of cell surface glycans. These enzymes catalyze the transfer of a phosphosugar from a soluble uridine diphospho-sugar (UDP-sugar) substrate to a membrane bound polyprenol-phosphate (Pren-P). The functional domains of PGTs belong to either the monotopic (monoPGT) or polytopic (polyPGT) superfamilies. The two superfamilies catalyze chemically-equivalent transformations, however they adopt distinct catalytic mechanisms. MonoPGTs are of particular interest because homologs are restricted exclusively to prokaryotes, highlighting an exciting opportunity for therapeutic focus. The monoPGT active site comprises a highly conserved Asp-Glu dyad and the “signature mechanism” involves a covalent phosphosugar adduct of a nucleophilic Asp-carboxylate (Nu-Asp) intermediate. This Nu-Asp activity is a hallmark of the mechanistic divergence of mono- and polyPGTs, which supports the development of small molecule probes with specificity towards monoPGTs. However, amino acids with carboxylic acid side chains (Asp, Glu) are among the least targeted amino acids for covalent inhibition. This is because small molecules targeting carboxylic acids have notoriously poor amino acid specificity, and amino acids that are more nucleophilic, such as cysteine or serine, can out-compete carboxylic acids for electrophiles. Recently, 2H-azirine (2H-Az) compounds have been developed as covalent and chemoselective probes for amino acids with carboxylic acid side chains.

  This work explores generating a diverse set of 2H-azirine compounds to chemically probe monoPGTs through covalent intervention. This involves developing modular synthetic routes for generating diverse libraries of 2H-azirine small molecules. New routes include generation of tunable carboxy-2H-azirines and α,β unsaturated 2H-azirines. Routes to generate 2H-azirines with varied alkyl chains are also explored as Pren-P substrates mimetics."

• Bio: Leah Seebald joined the faculty at Haverford College in 2022 as an Assistant Professor in the Department of Chemistry. Prior to this, Leah obtained her B.S. in Chemistry from the University of Pittsburgh where she did undergraduate research with Prof. Geoffrey Hutchison calculating piezoelectric conformational changes of rationally designed molecules. After completing her undergraduate degree, she worked for two years at a clinical diagnostics lab identifying pancreatic cancer and Barrett’s esophagus from patient samples. From this clinical experience Leah developed an interest in the connection between chemical research and human health, which led her to pursue her PhD at SUNY Albany working with Prof. Maksim Royzen. Leah’s graduate work involved designing and synthesizing novel paramagnetic probes for the study of RNA-protein interactions by NMR. From there, Leah joined Prof. Barbara Imperiali’s lab at MIT where she worked to develop and synthesize various types of probes for studying enzymes involved in glycan biosynthesis. This involved work with both covalent probes (activity-based protein profiling probes) and non-covalent probes (mechanistic probes) selective for bacterial phosphoglycosyl transferases and glycosyltransferases.

  Leah joined Haverford College and started her lab during the summer of 2022. Today the Seebald lab is focused on synthesizing covalent probes with novel electrophilic warheads for activity profiling phosphoglycosyl transferases. Leah hopes that her work in biorthogonal chemistry and glycan biosynthesis will really “click” for her students at this undergraduate only institution, and inspire the next generation of young glycoscientists.

  Read more about the work in her lab at her website.

• Abstract: Bacterial biofilms are a public health threat because they cause chronic and hospital-acquired infections but are resistant to antibiotics. Failure to characterize the biochemical machinery that drives biofilm dispersal risks missing key targets for treatment of infectious disease. Although nitric oxide (NO)-triggered biofilm dispersal in many bacteria, including Pseudomonas aeruginosa, a principal pathogen in cystic fibrosis and hospital-acquired infections, is well documented, the underlying biochemical processes responsible are not understood. Our laboratory has established a role for NO-regulation of biofilm in two different families of NO-sensitive hemoproteins, H-NOX (heme-NO/oxygen sensing protein) and NosP (NO sensing protein; discovered in our laboratory). Our current work is focused on the role of NO in regulating biofilm and virulence in P. aeruginosa through the GacS/Rsm motility/virulence switch and quorum sensing. Evidence from biochemical characterization of proteins in the NosP signaling pathways, as well as genetic and biofilm growth studies will be presented.

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• Abstract: Semiconductor nanocrystals have promise in many optoelectronic and electronic technologies due to their tunable electronic structure and facile colloidal processing. However, one major factor limiting their widespread adoption is inherent heterogeneity within an ensemble. For this reason, magic sized clusters, with atomically precise structures and negligible heterogeneous broadening, have drawn significant attention as a potential system with ensemble level homogeneity. However, many of the most common nanocrystal materials, such as Cd-chalcogenides and In-pnictides, form clusters with bandgaps far to the blue, limiting potential applications. We illustrate the colloidal synthesis of nontoxic, earth abundant, iron sulfide clusters with narrow and invariant absorption features and a ~700 nm band-gap which allows for absorption across the visible spectrum. These ~2nm diameter particles exhibit quantum confinement, with a blue shift from the expected 0.95 eV bandgap. Further growth in polymerizing media (e.g. oleyl amine) facilitates the formation of long-range order into quasi-1D fibrils. The formation of these fibrils coincides with a red-shift to the absorption spectrum while maintaining the apparent morphology of the individual nanocrystals. These iron sulfide clusters show promise as a platform for future device engineering due to the unique combination of optical properties and material availability and safety.

• Bio: Katherine E. Shulenberger began her chemistry journey at Wellesley College where she received her B.A. in chemistry in 2014. During her time at Wellesley she conducted astrochemistry research in the Arumainayagam lab. She then enrolled in the doctoral program in chemistry at MIT. Working in both the Bawendi and Tisdale research groups, her interests centered on understanding highly excited states in semiconductor nanocrystals. After receiving her PhD in 2019, she moved on to pursue further studies in the Dukovic group at CU Boulder as a postdoctoral scholar. During her time at CU, Dr. Shulenberger received a Cottrell postdoctoral fellowship and was named the CU Outstanding Postdoc of the year. Dr. Shulenberger joined the faculty at Brandeis University in the summer of 2023 as an assistant professor of chemistry. Her research group continues to push the boundaries of how we understand nanocrystal systems through the use of both novel photon-counting measurements and ultrafast optical characterization to bridge the gap between existing ensemble and single-particle techniques.

Abstract: Investigating the Mechanistic Nuances of Nucleophilic Aromatic Substitution

Nucleophilic aromatic substitution (SNAr) is broadly used in the synthesis of pharmaceuticals and other organic compounds.  These reactions have long been assumed to be stepwise, but recent studies have demonstrated that many SNAr reactions are in fact concerted.  Our lab has investigated the relationship between substrate structure and mechanism for a subset of SNAr reactions, and we have discovered that these SNAr reactions actually lie on a mechanistic continuum between stepwise and concerted extremes.  This presentation will highlight (i) the ways in which structural variations in the substrates, including electronic perturbations, acidity, and hydrogen bonding capability, influence the mechanism of SNAr, and (ii) how these mechanistic nuances can be unveiled using physical organic chemistry techniques such as reaction kinetics, linear free energy relationships, kinetic isotope effects, and computational chemistry.       

Abstract: Characterizing the interaction of huntingtin peptides with model lipid membranes 

Huntington’s disease (HD) is an inherited neurodegenerative disorder associated with motor and cognitive decline, caused by an expansion in the poly-glutamine (polyQ) region near the N-terminus of the huntingtin (htt) protein that results in inclusion body aggregates of mutated protein. There is increasing evidence that lipid interactions play a role in the toxic gain of function associated with htt polyQ expansion, as membrane-related changes, including structural abnormalities of several organelles, are observed in HD. The interactions between htt and lipid membranes were measured with a combination of circular dichroism, lipid monolayer compression isotherms, permeability assays, and fluorescence microscopy. Our data suggests that polyQ flanking regions play a critical role in htt binding and aggregation on lipid membranes. This peptide binding serves to soften, and sometimes permeabilize, the membrane. Inclusion of negatively charged membrane components, POPG and POPS, facilitates htt binding to the lipid interface, with the amount of binding scaling with increased negative charge. Salt screening experiments suggest the htt-membrane interaction is mediated by the hydrophobic effect and electrostatics. Additionally, we show that htt curvature sensing is driven by bulky sidechains of phenylalanine residues, which are able to sense lipid packing defects in the curved regions of the membrane.