2020 Program Important Dates

Informational Session:
November 12,  2019, 5:30pm, GCIS W105

Application Deadline:
Monday, January 27, 2020, 5:00pm

Student Interviews:
Week of February 10
(time and location TBA)

Awards Announced:
Week of February 24

Program Begins:
Beginning of Summer Quarter, Monday, June 22

Beckman Scholars Meeting, Irvine CA:
Tentative date: August 6-8

THE BECKMAN SCHOLARS PROGRAM

Do you do research in a faculty lab here at UChicago? Do you want to do research in faculty lab here? How would you like to be in a program designed to maximize your research experience?

Then, the Beckman Scholars Program (funded by the Arnold and Mabel Beckman Foundation) in Molecular Sciences might just be what you’re looking for.

This program is meant to provide students in the College the best opportunity to develop the skills that will promote their success during graduate and post-graduate training and begin building tools for independence and leadership. In addition to working in the laboratory of a UChicago mentor you will meet regularly with other undergraduate researchers on campus to develop judgment, insight and critical thinking skills.

The Beckman Scholars Program is aimed towards current Second-year students in the College, or Third-years who commit to working in his/her mentor’s lab for two full summers.  The program provides a total award of $21,000, as follows:

Summer fellowships ($6800 each summer) $13,600
Academic year fellowship 4,600
Travel and supply award 2,800

Full-time commitment is required during the summers; you may not take courses nor can you hold another paying job. Beckman Scholars must be US citizens or permanent residents.

All Beckman Scholars are required to attend the Beckman Scholars Symposium sponsored by the Arnold and Mabel Beckman Foundation, held annually at the Arnold and Mabel Beckman Center of the National Academies of Sciences and Engineering in Irvine, California in early August. During the second summer in the program, Beckman Scholars present the results of their work as posters or platform presentations.

Program Application

To apply for the Beckman Scholar Program, complete the application form.

The application can be downloaded here:

In addition to the application form, please include:

  1. A one-page statement of your career goals and reasons for participating in the Beckman Scholars Program.
  2. An official U of C transcript. Use the UChicago Document Delivery Service (Parchment) to have an official transcript sent to jfeder@uchicago.edu
  3. A 3-page research proposal, exclusive of references and figures, describing the project, including an experimental approach.
  4. A letter of recommendation and commitment from the mentor.
  5. A letter of recommendation from another U of C faculty member or a previous research mentor .
  6. Your Curriculum Vitae

MENTORSHIP AND OVERSIGHT

The Beckman Scholars Program in Molecular Sciences is overseen by a faculty Director, who chairs the Beckman Scholar Steering Committee and an Administrative Director.

Director
John Anderson Ph.D., Asst. Professor, Dept. of Chemistry

Steering Committee
Stephen J. Kron M.D.-Ph.D., Professor, Dept. Molecular Genetics and Cell Biology

Administrative Director
Julie Feder, Ph.D., Executive Administrator, Institute for Biophysical Dynamics

Beckman Scholars must do research in the lab of one of the outstanding faculty members, listed below. They have all chosen to mentor undergraduates in this program and come from a variety of departments in the physical and the biological sciences. The group includes faculty recognized by the highest teaching awards at UChicago–the Llewellyn John and Harriet Manchester Quantrell Award for Excellence in Undergraduate Teaching, the Faculty Award for Excellence in Graduate Teaching and the J. and J. Neubauer Junior Faculty Development Award. All have vigorous, nationally-funded research programs with an stellar record of mentoring undergraduates in their research areas.

Beckman Scholar Faculty Mentors

 

John Anderson, Program Director
Assistant Professor, Chemistry 

 

Erin Adams
Professor, Department of Biochemistry & Molecular Biology

 

Bryan Dickinson
Assistant Professor, Chemistry

 

Guangbin Dong
Professor, Department of Chemistry

 

Gregory Engel
Professor, Department of Chemistry

 

Lucy Godley
Professor, Department of Medicine

 

Jean Greenberg
Professor, Department of Molecular Genetics & Cell Biology

 

Chuan He
Professor, Department of Chemistry

 

Stephen Kron
Professor, Department of Molecular Genetics & Cell Biolog

 

Ka Yee Lee
Professor, Department of Chemistry

 

Wenbin Lin
Professor, Department of Chemistry

 

Ilaria Rebay
Professor, Ben May Department for Cancer Research

 

Scott Snyder
Professor, Department of Chemistry

 

Bozhi Tian
Associate Professor, Department of Chemistry

 

Xiaoxi Zhuang
Professor, Department of Neurobiology

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

PAST U OF C SCHOLARS

2016-17

Ellen Iverson

Ellen Iverson

Honors: National Science Foundation Graduate Fellowship

“CRISPR as an Innovative Tool for Studying Senescence-Associated Aging in the Lung”

In recent years, studies have linked cellular senescence to pathologies associated with aging tissue, including serious lung conditions like chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Improving understanding of the factors that accelerate the development of senescence may help suggest new treatment options for such diseases. In particular, compounds that may be able to delay or prevent the onset of senescence have exciting potential. To this end, I purpose to develop a CRISPR-Cas9 construct capable of inducing a dose-dependent amount of pure DNA damage without any of the secondary effects associated with drugs or radiation. This tool can then be tested in murine lung fibroblasts for its ability to induce senescence alone and in combination with reactive oxygen species (ROS), allowing new and important insight into the relationship between DNA damage, ROS, and senescence. I will then use these data to design and demonstrate the efficacy of a screen for possible modulators of the onset of accelerated senescence in the lung.

Andrew Molina

Andrew Molina

“Molecular Mechanism of CNS Myelinogeneis: Self-Assembly of Lipid Nanotubes and Nanotube Bilayer Dynamics”

My research interests center around the biophysical process of self-assembled structures formed by lipid and lipid/protein mixtures associated with Central Nervous System (CNS) myelinogenesis. The myelin sheath is a layer of insulation consisting of a mixture of proteins and lipids that surrounds the axons of neurons, and allows for the rapid transmission of electrical impulses throughout the body. This functionality is disrupted in patients suffering from demyelinating diseases such as multiple sclerosis, in which the myelin sheath breaks down and the propagation of the electrical impulse is significantly compromised. Specifically, my research objective is to re-examine the mechanism of myelin sheath formation and elucidate the role of plasmalogen, phospholipids, glycolipids, cholesterol, galactocerebrosides, sulfatides, and myelin-specific proteins in the formation of tubular structures recently observed around developing CNS myelin sheaths. Using transmission electron microscopy, I aim to find the optimal conditions and ratios of myelin constituents for spontaneous tubule self-assembly in an attempt to recreate in vitro tubule structures observed in vivo. I further plan to use atomic force microscopy to examine the driving forces behind the transition of these self-assembled structures from tubules into multilamellar structures characteristic of a mature myelin sheath.

2014-15

Theresa Hwang

Theresa Hwang

Currently at MIT’s Biology PhD Program, Keating lab

“Photoswitchable affinity clamps: Modulating protein activity with light”

Optogenetics, the study of using genetically-encoded, light-controllable molecules to manipulate living systems, provides biologists with an extremely powerful way to control and observe cellular behavior. Hence, the challenge to broaden the range of cellular processes optogenetic tools can address is an interesting and pressing one. I propose the creation of a light-controllable affinity clamp whose binding affinity towards a target, can be modulated by light. Affinity clamps are novel binding proteins developed in the Koide lab that feature a unique clamshell like architecture. These clamps are a transformative solution in the quest to generate high affinity reagents that can bind to short, unstructured peptide segments present in biologically significant protein molecules, such as post-translation modification sites (PTMs). Hence, the coupling of light to allosterically control affinity clamps presents the possibility of a very potent tool that can link cellular processes with cellular behavior. The immediate goal of this project will be proof-of-concept, as light-controllable affinity clamps have never been produced. The creation of such a protein, and ultimately being able to control its behavior in cells through light dependent association and dissociation of the clamp to its targets, will allow us to determine a reliable method to rationally and systematically convert clamps into powerful cellular perturbation tools. This project will be accomplished through three aims: (1) the cloning and expression of a light-controllable affinity clamp, (2) modulating its binding affinity in vitro, and (3) testing its light-controllable activity in vivo. We can then extend the conclusions gained from this project to create a wide variety of clamps that can modulate PTM-dependent signaling.

Trevor Roberts

Trevor Roberts

Current Institution: University of California, Berkeley
Program: Ph.D. in Chemistry
Honors: National Science Foundation Graduate Fellowship

“Product Branching of CH2CH2ONO Radical at 193 nm Using BrCH2CH2ONO”

The experiments I proposed are designed to determine whether BrCH2CH2ONO can be utilized as a photolytic precursor to generate the CH2CH2ONO radical, a radical of potential importance in atmospheric chemistry, and to probe the unimolecular dissociation channels of that radical. Unlike at 351 nm excitation, which only cleaves the O-NO bond in BrCH2CH2ONO, we expect that excitation at 193 nm to raise BrCH2CH2ONO to an excited state repulsive in the C-Br bond that should allow us to photolytically cleave the C-Br bond. Radicals are difficult to study under bulk conditions due to their high reactivity, so employing collision free conditions allows for the study of particular radicals like CH2CH2ONO. If our initial experiments show that C-Br photofission occurs in some of the photoexcited molecules, we can then study the subsequent unimolecular decomposition of the CH2CH2ONO radical. In particular, two different product channels might occur, one producing NO and the other producing NO2. NO and NO2 are atmospherically abundant and responsible for facilitating numerous reactions; they play an important role in the ozone cycle. My proposed experiments use a crossed laser-molecular beam scattering apparatus with electron bombardment detection of the photofragments, resolving their velocity distribution to allow us to separate the NO formed in primary O-NO photofission from the NO produced from the unimolecular dissociation of BrCH2CH2ONO radicals. The measured recoil kinetic energies allow us to first determine the internal energy distribution of the nascent radicals, using conservation of energy and momentum. Then we can probe the energetics of the CH2CH2ONO radical decomposition product channels. The experiments, thus, give a deeper scientific understanding of potentially significant atmospheric mechanisms.

2013

Mara Farcasanu

Mara Farcasanu

Wei-Jen Tang Group

“Exploring the Structure and Biochemical Activity of the Free-State Anthrax Edema Factor Protein”

Edema Factor (EF) is an exotoxin secreted by the anthrax-causing bacteria Bacillus anthracis and plays an essential role in the progress of the disease within a cell. Upon entering the cell, EF is activated as an adenylyl cyclase by binding to calmodulin (CaM). Although the structure of active EF has been determined, the structure of inactive EF is not definitively known. To study both the structure and biochemical function of EF, it is important to begin with an understanding of the inactive EF’s structure. Because the protein must unfold in order to enter the host cell, EF is recalcitrant to crystallization without the stability provided by CaM. Thus, it will first be important to find specific chaperones that will stabilize the protein. I propose to perform in vivo biotinylation and purification of EF, followed by a search for an antibody that would bind to EF with high affinity, made possible by collaboration with the Shohei Koide group. The stability provided by such high-affinity binders should aid in the crystallization of EF. Once appropriate antibodies and buffers are identified and crystallization has been successful, diffraction data for the crystals will be obtained at Advanced Photon Source at Argonne National Laboratory. Furthermore, the antibodies’ effect on EF’s function and activity can be analyzed by measuring in vivo cAMP concentrations of affected cells and through an enzymatic assay. Success in these aims will thus yield not only a structure of the CaM-free EF, but also provide insights towards a possible EF-based therapeutic against anthrax infection.

Isaac Larkin

Isaac Larkin

Sean Crosson Group

“Respiration and a Putative Carbon Monoxide Dehydrogenase in Caulobacter crescentus”

Aerobic carbon monoxide dehydrogenase is an oxygen-stable enzyme that enables some bacteria to use carbon monoxide as an energy and a carbon source, and has potential applications to the sensing and degradation of CO in homes and industrial pollution. We have found genes that code for the L and S subunits of a putative carbon monoxide dehydrogenase in Caulobacter crescentus. We propose a project that uses protein engineering tools to purify the L and S subunits and pull down and characterize the missing M subunit. We will then use an anaerobic hemoglobin-based assay to determine the activity of the putative carbon monoxide dehydrogenase. In parallel, we will grow knockout and overexpression strains of the putative carbon monoxide dehydrogenase in C. crescentus, and determine via outgrowths in gas-tight ampoules containing different mixtures of air, argon, and CO whether C. crescentus can consume CO as a carbon or an energy source, and whether it requires the putative carbon monoxide dehydrogenase to do so.

2012

Kathleen Bohanon

Kathleen Bohanon

Chuan He Group

 “Identification of 5-Hydroxymethylcytosine Binding Proteins in Mammalian Brain Tissue”

Epigenetic DNA modifications play an essential role in brain function and are altered in various neurological disorders. The exact function of 5-hydroxymethylcytosine (5hmC), a recently discovered DNA modification that comprises 40% of modified cytosine in the brain, remains obscure due to inadequate techniques for precisely mapping it in genomic DNA. Utilizing the recently developed Tet-assisted Bisulfite Sequencing (TAB-Seq) method, it is possible to examine previously detected 5hmC-enriched loci with single-base resolution. The sequences found to be enriched with 5hmC will be used to design nucleic acid probes in order to pull down proteins that selectively bind to 5hmC. Since the presence (or absence) of this modification may affect the recruitment of various proteins, these results may illuminate the role that 5hmC plays in transcriptional regulation.

Christopher Delaney

Christopher Delaney

Shohei Koide Group

“Engineering Phosphotyrosine-Specific Affinity Clamps and using them to Dissect Cancer Signaling Pathways”

The goal of this project is to enhance our understanding of phosphotyrosine (pY) signaling by developing engineered proteins and using them to dissect individual pY signaling pathways. Modern protein engineering focuses on creating novel biomolecular tools with scientific and medical applications. However, generating useful binding proteins with high affinity and specificity is challenging when targeting short epitopes or distinguishing between similar peptide motifs. Engineered proteins (termed affinity clamps) being developed in the Koide group, provide an innovative solution to these problems in that they demonstrate both exquisite binding affinity and specificity to typically elusive targets. For instance, affinity clamp technology could more easily produce binding proteins that recognize specific phosphorylated tyrosine residues, or pY sites, than could general protein engineering. Such pY-target affinity clamps would greatly benefit medical and biological research given the implications of rogue pY signaling in many cancers. Specifically, pY-targeted affinity clamps will help piece together the intricacies of pY signaling by binding to and blocking specific pY residues.

2009

Jason Hao

Jason Hao

Kozmin Group

“The Synthesis of Scaffold-Unbiased Small Molecule Libraries”

This project proposes to use the methods of diversity oriented synthesis (DOS) to produce a library of compounds aimed at the discovery of new bioactive chemotypes. The chemical scheme begins with a 1,6-enyne, which through catalyst enabled diversification and selective [4+2] Diels Alder reactions may yield 25 cycloadducts, all of which have an unsaturated double-bond suitable for epoxidation. This project intends to further diversify these adducts via two possible pathways. In the first scheme, the epoxide is opened with a choice of 5 amino acids and then subsequently condensed with an additional amino acid to yield a dipeptide substituent to the main scaffold. Cyclization of the terminal carboxylic acid with the epoxide hydroxyl group will then yield a final library of 500 (20x5x5) compounds consisting of 180 diverse scaffolds. An alternative method lies in the epoxide opening via the alkynide form of the 1,6-enyne, which by further catalyst enabled diversification and cyclization will yield a 300 member library consisting of 300 different polycyclic scaffolds. The compound members will then be subjected to a high-throughput cell-based screen for the identification of novel small-molecule inhibitors of glycolysis.

Vasilios Kalas

Vasilios Kalas

Wei-Jen Tang Group

“Exploring the Molecular Bases of Substrate Recognition and Degradation by Human Insulin-Degrading Enzyme”

Insulin-degrading enzyme (IDE) is a metalloprotease that demonstrates a remarkable ability to recognize and degrade functionally and structurally diverse bioactive peptides such as insulin and amyloid-beta (Aβ) yet exhibits high selectivity and affinity to the targeted substrates. While many of this protease’s unique structural properties have been studied extensively in understanding its catalytic versatility, the mechanism by which IDE binds and degrades structurally diverse peptides remains elusive. To gain a better understanding of this intriguing mechanism, this project will investigate two critical factors – substrate size and “unfoldability” – that contribute to the substrate specificity and degradative pathway of IDE. To study the effects of these factors, I use opioid peptides and ubiquitin variants as the model substrate systems. First, by using opioid peptides that have identical N-terminal sequences but are variable in size, I propose to examine the effect of substrate size, in amino acid length, on the binding and cleavage of substrates by IDE. Preliminary kinetic analyses indicate that longer opioid peptides bind more tightly to but are degraded less rapidly by IDE than shorter ones. To explain this effect, prospective X-ray crystallographic studies will attempt to resolve the differences in binding interactions between IDE and opioid peptides of varying length. Second, I aim to manipulate the propensity of unfolding of ubiquitin, which is normally not degraded by IDE, and examine if “unfoldability” is a prerequisite for a peptide to be a substrate of IDE. Indeed, our preliminary data using mass spectrometry analyses reveal that wild type ubiquitin, which is extremely stable, cannot be degraded by IDE. However, two ubiquitin variants that have the correct folded structure but have a high tendency to convert to the unfolded state are effectively degraded by IDE. Understanding the role of the unfolded substrate intermediate in the degradative pathway of IDE’s action is crucial in explaining IDE’s catalytic versatility. Success in these aims together with the demonstration of the in vivo relevance of such protein-protein interactions would drive scientists to the design of inhibitors of IDE activity that could serve as therapeutics or preventatives to serious chronic diseases, such as opiate addiction, diabetes, and Alzheimer’s disease.

2008

Carl Brozek

Carl Brozek

Gregory Hillhouse Group

Current Institution: MIT / Ph.D. in Chemistry
Honors: National Science Foundation Graduate Fellowship

“The Search for a Terminal Ni Oxo Complex”

While early-metal oxo complexes (M=O) are common and demonstrate interesting reactivity, late metal complexes are unobserved. Recently, the Hillhouse group synthesized the d8 imido complex 1,2-bis(di-tert-butylphosphino) ethane)Ni=NAr. Attempts to synthesize the analogous d8oxo led to rapid decomposition to an oxidized phosphine. Though unsuccessful, these results strongly suggested a Ni(II) oxo intermediate. This project will focus on the isolation of a Ni=O complex by introducing a more rigid backbone in the chelated phosphino ligand to prevent intramolecular migration of phosphorus to oxygen.

The reactivity of the d8 imido complex suggests that the Ni(II) oxo will have interesting reactivity worth investigating.

The goal of the project is to synthesize an L2Ni=O complex using a naphthalene-based bis(phosphine) ligand (L2) instead of the more flexible ethylene backbone.

Dan Houle

Dan Houle

Chuan He Group

“Chemical Cross-Linking to Study the Electrostatic Switching Mechanism of E. coli N-Ada”

In order to prevent mutagenic damage to the genome by cellular or environmental alkylating agents, many organisms have evolved a set of DNA repair proteins that search for and repair these covalent modifications. Escherichia Coli N-Ada is an exemplary DNA repair protein, serving a dual role in methylation resistance: it first acts to repair methyl phosphotriester damage by directly transferring a methyl group from the DNA backbone to its tetrathiolate zinc(II) active site. Upon this methylation, N-Adas affinity to DNA increases 100-1000 fold, allowing it to bind sequence specifically to the ada promoter, initiating transcription of a collection of methylation resistance proteins.

This mechanism of adaptive response is responsible for E. Colisremarkable ability to resist methylation damage. The main goal of this project is to develop a mechanistic explanation for the drastic increase in DNA affinity upon methylation of N-Ada. An electrostatic switching mechanism was proposed,1in which methylation reduces the electrostatic repulsion between DNA and the active site. By obtaining an X-ray crystal structure of unmethylated N-Ada bound to dsDNA, the electrostatic interactions of the complex can be compared to the crystal structure of methylated N-Ada bound to DNA, which was published in 2005.1 Observing the electrostatic and structural features of the complex in methylated and unmethylated forms is key to understanding the change in DNA affinity.

Also of interest is to understand why Cys38 (of the four active site cysteines) is selectively methylated during methyl phosphotriester repair. Structural features of the active site that will be clear in the crystal structure will explain this regioselectivity.

A variety of biological and chemical methods will be employed; most notably, a disulfide chemical crosslinking strategy will be used to stabilize the protein/DNA complex.

1) He, C., Hus, J.C., Sun, L.J., Zhou, P., Norman, D., Dotsch, V., Wei, H., Gross, W., Wagner, G., and Verdine, G. (2005). A Methylation-Dependant Electrostatic Switch Controls DNA Repair and Transcriptional Activation by E. coli Ada. Mol. Cell. 20, 117-129.

2007

Donnie Bungum

Donnie Bungum

Gregory Hillhouse Group

Honors: Goldwater Scholar, Marshall Scholar

“Synthesis of 61Ni compounds for Mossbauer spectroscopy”

Mossbauer Spectroscopy is one of the most powerful tools available for characterization of metal-containing compounds. Based on a Nobel Prize winning principle of high-energy physics discovered by Dr. Rudolf Mossbauer, this technique allows researchers to determine the oxidation state, electronic environment, spin state, symmetry, and magnetic properties of compounds containing one of the 100 or so Mossbauer-active metals. Nearly 90% of the literature on Mossbauer spectroscopy published to date concerns Fe species, as this isotope of iron can be studied in a wide range of chemical environments under varied experimental conditions.

In recent years, however, improvements in technology have opened the door to new applications of Mossbauer spectroscopy to metal species once difficult to study. One of these newly accessible Mossbauer-active isotopes is  61Ni, an exciting development due to nickels important role in chemical, biological, and industrial processes. As with any spectroscopic technique, characteristic bonds, geometries, and symmetries exhibit distinctive absorption spectra that can be used to characterize and identify compounds. Using the methods on inorganic synthesis, this research project seeks to contribute to the development of  61Ni Mossbauer spectroscopy by providing characteristic compounds for spectroscopic analysis.

Emily Jane Glassman

Emily Jane Glassman

Laurie Butler Group

Current Institution: University of California, Berkeley
Program: Ph.D. in Chemistry
Honors: National Science Foundation Graduate Fellowship

“Investigation of the Unimolecular Dissociations of CH3OSO and CH3SO2 Radicals”

The reactions of the CH3SO2 and CH3OSO radicals are particularly important processes to understand in the fields of combustion and atmospheric chemistry. As coal-burning technologies expand, it becomes imperative to understand the dynamics of reactions involving sulfur, one of the major components of coal. The radicals and their products, CH3, CH3O, SO, and SO2 play a significant role in the atmospheric oxidation cascade of dimethyl sulfide, a major natural source of sulfur. However, the energy barriers for the unimolecular dissociations of CH3OSO and CH3SO2 have never been positively determined. In this study, we propose to investigate the generation of these important

radicals, CH3OSO and CH3SO2 from appropriate photolytic precursors, methyl sulfonylchloride, CH3SO2Cl and methylchlorosulfinate, CH3OSOCl, respectively. Our planned measurement of the velocity distribution of the Cl atom co-fragment allows us to determine the nascent internal energy distribution in the CH3SO2 radicals produced at 193 nm, allowing us to benchmark the temperature-dependent unimolecular dissociation rate of the radicals.

Further planned studies at lower internal energies promise a direct determination of the energy barriers for dissociation of each radical to CH3 + SO2 by determining the velocity distribution, and thus the internal energy distribution, of the radical intermediates which do not dissociate. We also seek to develop a fundamental understanding of these reactions from first-principle quantum mechanics. Prior experimental work in our lab with complementary electronic structure calculations showed that for CH3OCO radicals, cleavage of the H3C-O bond in the cis-conformer traversed a much lower barrier than for the trans- radical. A natural bond orbital analysis of orbital interactions along the cis reaction coordinate yielded a compelling physical explanation for the experimental observation. We would like to explore the extension of this to sulfur-containing systems.

2006

John Anderson

John Anderson

Gregory Hillhouse Group

Current Institution: MIT
Program: Ph.D. in Chemistry
Honors: National Science Foundation Graduate Fellowship

“Exploring the Biologically Inspired Chemistry of Nickel(I)”

My research is focused on using nickel systems involving the chelating ditertbutylphosphinoethane (dtbpe) ligand system to reproduce some proposed biological intermediates in the laboratory. This system has already been used extensively to explore a number of interesting nickel complexes ranging in oxidation state from zero to three. I will be studying nickel one in particular due to the biological significance of this oxidation state.

Nickel is believed to be an important oxidation state in both the acetyl coenzyme a synthase/carbon monoxide dehydrogenase (ACS/CODH) and the nickel superoxide dismutase (NiSOD) enzymes.

ACS/CODH is responsible for the synthesis of acetyl coenzyme A, an important biological building block. NiSOD catalytically degrades harmful superoxide molecules into less reactive peroxide species. Its role within these biological systems is still unclear, but a number of interesting nickel compounds are proposed as intermediates within these systems including nickel oxo, acyl, carbonyl, and alkyl species.

(dtbpe)NiOTf (OTf = triflouromethanesulfonate) has shown the ability to undergo facile two electron oxidation from Ni (I) to Ni (III). Utilizing this useful synthetic pathway I will attempt to access nickel oxo and peroxo moieties as well as determine whether this species can bind various small molecules such as carbon monoxide and carbon dioxide. Further studies will also be conducted to determine whether a nickel acyl species is accessible either from nucleophilic attack on a nickel carbonyl or by migratory insertion of carbon monoxide into a nickel alkyl bond. Nucleophilic attack by a sulfur species will be tested to see if a thioester can be obtained from a nickel acyl species. If these molecules can be synthesized there is a possibility of gaining insight into the proposed intermediates within these important biological systems.

James Fitzgerald

James Fitzgerald

Tobin Sosnick Group

Graduation Date: 2007
Current Institution: Stanford University
Program: Ph.D. in Physics
Honors: National Science Foundation Graduate Fellowship

“Optimal Coordinate Systems and the Backbone Dependence of Energy Functions used for Protein Folding Simulations and Structure Prediction”

Our overall goal is to create an energy function to address currently inaccessible problems in protein folding and binding. Statistical potentials specify the “energy” of a protein structure based upon statistics obtained from a library of protein structures. The energy is assigned according to the Boltzmann distribution. The benefits of this approach are immediately clear. Rather than explicitly including physical interactions between atoms or groups of atoms, statistical mechanical concepts are used to relate the probability of occurrence to the energy, so the precise forms of the interaction potentials are irrelevant. Moreover, by using a statistical potential, realistic modeling of the solvent becomes unnecessary, thereby providing another enormous computational simplification.

However, in order for statistical potentials to be computationally useful, the assumption is made that energies are pair-wise additive (the total energy is the sum of the energies of each pair of atoms). This assumption is only an approximation, and this approximation can introduce considerable errors. Hence, when building a statistical potential, a major goal is to diminish these errors as much as possible.

The first step is to improve the existing energy functions used in the Sosnick and Freed labs by adding dependences on backbone geometry and amino acid environment. By including this extra information, some of the physical information that is abandoned for the computational simplicity of pair interactions can be regained. Ultimately, interactions between groups of atoms will be parameterized in a form that considers their relative orientation. This alteration naturally stresses the importance of the orientation of bond vectors, and should lead to a more accurate separation of the energy into a pair-wise additive form.

More on James’s work.

Amy Winans

Amy Winans

Ka Yee Lee Group

Current Institution: Stanford University
Program: Ph.D. in Biophysics
Honors: National Science Foundation Graduate Fellowship

“The Effects of GM1 Ganglioside- and Cholesterol- Containing Membranes on Amyloid-β Binding and Aggregation”

My works focuses on how the addition of gangliosides (specifically monosialic ganglioside: GM1) and cholesterol to a model cell membrane mediates the interaction between the membrane and the amyloid-β protein. (A-β). A-β has been identified as the protein composing the amyloid plaques found deposited in the brains of Alzheimer’s patients. Under physiological conditions, the A-β protein folds into a random coil. In amyloid plaques however, A-β is found deposited in cross-linked β-sheet conformation. A growing body of research has provided evidence for a link between cell membranes and A-β aggregation into β-sheet fibrils. Interaction with the cell membrane may also be the way in which A-β exerts its neurotoxic effects.

I propose to clarify the effects of GM1 and cholesterol on A-β activity in the presence of model lipid membranes using the following assays to monitor different levels of A-β activity:

  • Circular dichroism: monitors the secondary structure of A-β.
  • Thioflavin T fluorescence: quantifies the amount of fibrillar A-β present in solution.
  • High performance liquid chromatography: monomeric A-β will be separated from bound A-β and then measured using a UV-vis spectrometer.
  • Dynamic light scattering: monitors vesicle size.

2005

Doran Bennett

Doran Bennett

Laurie Butler Group

Graduation Date: 2007
Current Institution: University of California, Berkeley
Program: Ph.D. in Chemistry
Honors: Goldwater Scholar , National Science Foundation Graduate Fellowship

“Ground State Nonadiabatic Dynamics in Combustion Intermediates: A Study of the Vinoxy →H + Ketene Product Channel”

The vinoxy radical (CH2CHO) has shown itself to be of both practical and theoretical interest. Its practical interest arises from combustion chemistry where vinoxy is an intermediate for a number of important reactions:

  • (1) O(3P) + C2H4i
  • (2) O(3P) + C2H3ii
  • (3) OH + C2H2iii
  • (4) OH + C2H4Oiv

These reactions are important because they are commonly found in the mechanisms for the combustion of larger aliphatic and aromatic compounds. The research I propose will probe the dissociation dynamics of the vinoxy radical by way of the potential energy surface (PES), illuminating the role vinoxy pays in the overall combustion process.

Vinoxy is of theoretical interest because it exhibits nonadiabatic effects in its ground state. Often in textbooks the general conception of the Born-Oppenheimer approximation is that it only fails when operating with ions of excited states. The Born-Oppenheimer approximation however is valid only if electrons are capable of rearranging fast enough (relative to nuclei) for the nuclear dynamics to completely decouple from the electronic motion. Thus, we expect this approximation to break down in any situation where the wave function is forced to undergo large changes over a small change in the nuclear coordinates. Vinoxy demonstrates this difficulty, as it is a small organic molecule with no particularly exotic groups attached to it, but it shows signs of extreme nonadiabatic suppression of a single channel in its ground state dynamics. This makes it of fundamental interest as an example of the failure of the Born-Oppenheimer approximation in a small organic molecule.

Michelle Rengarajan

Michelle Rengarajan

Steve Kron Group

Graduation Date: 2007
Current Institution: Stanford University
Program: M.D. / Ph.D.
Honors: Medical Science Training Program Fellowship

“Using molecular modeling and structural screens to identify potentially novel inhibitors of Saccharomyces cerevisiae cyclin-dependent kinase Cdc28”

A vast body of protein structural data and sequence information has in recent years been made available for a wide variety of organisms. Before attempts to process this information experimentally, molecular modeling can be a powerful tool to mine and utilize this otherwise overwhelming body of data. In particular, molecular modeling of proteins can be used to search for structural components conserved across species or components which, if mutated, result in a compensatory mutation in an interacting partner. I propose to use ab initio modeling, homology modeling and structural screens to search for inhibitors of Cdc28 Saccharomyces cerevisiae cyclin-dependent kinase (CDK), which is involved in the transition between the G1 and S phases of the cell cycle.

When a cell detects DNA damage, its cell cycle temporarily stops so that DNA can be repaired; this phenomenon is called checkpoint and the machinery that drives it is often mutated in human cancers. Yeast could provide a simple system in which to examine G1 checkpoint, however, despite extensive study of G1 checkpoint in mammals, the pathways involved have not been fully elucidated in yeast.

The yeast cell cycle is governed by a master regulator, a cyclin-dependent kinase (Cdk) called Cdc28. At different times, Cdc28 partners A- and B-type cyclins (Clns and Clbs, respectively) to yield different substrate specificity. While Sic1, the inhibitor of Cdc28-Clb complexes, is well-characterized, the inhibition of Cdc28-Cln complexes is not fully understood. With my work, I hope to elucidate this inhibitory mechanism.

2004

Joshua D. Tice

Joshua D. Tice

Rustem Ismagilov Group

Graduation Date: 2005
Current Institution: University of Illinois, Urbana, Champaign
Program: Ph.D. in Chemistry

“Nanoliter droplet-based microfluidic system for evaluating protein crystallization conditions with on-chip diffraction”

Growing high-quality crystals of proteins and other biological macromolecules plays an important role in the determination of tertiary structure. Crystallization conditions are usually identified by screening a large number of assays with variable ratios of solutions of the protein, precipitants, and other additives. Microfluidic technology presents an opportunity to improve this process by reducing the amount of protein needed, reducing labor, and making it economically feasible for use in individual laboratories. A microfluidic system, comprising a network of channels fabricated in poly(dimethylsiloxane) (PDMS) and a glass x-ray capillary, was used to perform protein crystallization trials in nanoliter-sized droplets.

Droplets containing protein, buffer, precipitant, and additive solutions were formed by flowing several reagent streams into a stream of fluorinated oil. The droplets were flowed into a glass capillary, which allowed crystallization trials to be performed by microbatch techniques by eliminating evaporation of solutions. It was also shown that by using a water-permeable carrier fluid and controlling diffusion of water between droplets, crystallization trials could be performed by vapor-diffusion techniques in the capillaries. Without manually manipulating the crystals, crystals were analyzed by X-ray diffraction directly on-chip. Additionally, recent results for performing droplet-based, free-interface diffusion crystallization experiments in capillaries will be presented. Overall, the described methods demonstrate potential to accelerate structural studies of proteins and also assist in crystallization of smaller organic and inorganic molecules and assist fundamental studies of crystallization phenomena.

2020 Program Important Dates

Informational Session:
November 12, 5:30pm, GCIS W105

Application Deadline:
Monday January 27, 5:30pm

Student Interviews:
Week of February 10th
(time and location TBA)

Awards Announced:
Week of February 24th

Program Begins:
Beginning of Summer Quarter, Monday June 22

Beckman Scholars Meeting, Irvine CA:
August 6-8 (tentative)