Teaching through Research: Alignment of Core Chemistry

Article Cite This: J. Chem. Educ. XXXX, XXX, XXX−XXX

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Teaching through Research: Alignment of Core Chemistry Competencies and Skills within a Multidisciplinary Research Framework Eman Ghanem,*,†,⊥ S. Reid Long,‡ Stacia E. Rodenbusch,† Ruth I. Shear,‡ Josh T. Beckham,† Kristen Procko,†,¶ Lauren DePue,† Keith J. Stevenson,*,‡ Jon D. Robertus,§ Stephen Martin,*,‡ Bradley Holliday,‡ Richard A. Jones,*,‡ Eric V. Anslyn,*,‡ and Sarah L. Simmons∥ †

College of Natural Sciences, The University of Texas at Austin, Austin, Texas 78712, United States Department of Chemistry, The University of Texas at Austin, Austin, Texas 78712, United States § Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas 78712, United States ∥ Howard Hughes Medical Institute, Chevy Chase, Maryland 20815-6789, United States ‡

S Supporting Information *

ABSTRACT: Innovative models of teaching through research have broken the long-held paradigm that core chemistry competencies must be taught with predictable, scripted experiments. We describe here five fundamentally different, course-based undergraduate research experiences that integrate faculty research projects, accomplish ACS accreditation objectives, provide the benefits of an early research experience to students, and have resulted in publishable findings. The model detailed is the Freshman Research Initiative (FRI) at The University of Texas at Austin. While there are currently 30+ active FRI research groups, or “streams”, we focus this report on five different chemistry streams in these four areas (organic, inorganic, analytical, and biochemistry) to demonstrate how general chemistry laboratory skills are taught in the context of these varied research disciplines. To illustrate the flexibility of the FRI model for teaching first-year chemistry, we show how each stream teaches students three different skills within the context of their research: making (synthesis), measuring (UV-vis spectroscopy), and characterization. As a unifying example, all five chemistry streams describe using UV−vis spectroscopy to characterize new synthetic molecules, complexes, and compounds, followed by extensive quantitative collection, processing, and analysis of experimental data sets. The FRI model allows full integration of training in mandatory and accredited general chemistry skill sets with open-ended research experiences with unexpected outcomes in undergraduate science curricula. In turn, this model enables undergraduates to be productive contributors to new knowledge and scientific discovery at the earliest levels of the undergraduate experience. KEYWORDS: First-Year Undergraduate/General, Curriculum, Laboratory Instruction, Interdisciplinary/Multidisciplinary, Inquiry-Based/Discovery Learning, Undergraduate Research, UV−Vis Spectroscopy, Synthesis

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INTRODUCTION Undergraduate introductory “general” chemistry course work is an integral component of science education because it provides the basic knowledge and foundation for advanced science courses.1 Traditionally, college science education has focused on classroom instruction coupled with standardized laboratory courses where students perform experiments with known outcomes. However, it has been demonstrated that this form of introductory chemistry lab courses is not the most effective model for educating students about the nature of science when compared to inquiry-based or research-based experiences.2 In the report to the President, Engage to Excel, the President’s Council of Advisors on Science and Technology (PCAST) set as a national priority the production of at least one million more STEM graduates in the next decade and recommended © XXXX American Chemical Society and Division of Chemical Education, Inc.

replacing standard laboratory courses with discovery-based research courses as one way to increase students’ interest and retention in STEM fields.3 Additionally, numerous studies have shown that students who become involved in research are more likely to enjoy, to succeed in, and to stay involved in science.4−6 Participation in authentic research guided by experiences with unexpected outcomes is now considered an essential part of science education.1,7 There are numerous examples of integrating research experiences into the undergraduate science curriculum.8−10 However, the majority of the currently available models exist in Primarily Undergraduate Institutions (PUIs) Received: April 30, 2017 Revised: November 21, 2017

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DOI: 10.1021/acs.jchemed.7b00294 J. Chem. Educ. XXXX, XXX, XXX−XXX

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and graduate students in overseeing focused research projects as educators, the use of PhD level scientists as research educators, and the use of faculty as integrators of teaching through research, which ultimately enhances and impacts the research capacity of the university. By integrating faculty research on campus with undergraduate curricula at scale, the model allows exponentially more students to experience the benefits of undergraduate research and to beneficially influence their choices and decisions leading to their ultimate career plans.13 The FRI addresses several issues that have historically hindered involvement of students, particularly underrepresented minorities, first-generation students, and those from low socioeconomic backgrounds in research: (i) FRI facilitates students’ communication with their families about research by discussing internship, fellowship, and postgraduate career opportunities; (ii) FRI integrates research into the undergraduate core science curriculum, so that research is not an extracurricular activity but instead is a mechanism for earning required lab course credits important for making progress in science majors; and (iii) FRI provides an infrastructure for students to build professional and peer support networks early in their college career. Thus, FRI integrates a combination of experiences that have been shown to contribute to student success: mentoring,14 peer mentoring,15 research experiences,4,5 and learning communities.16 In this report, we will illustrate the versatility and effectiveness of the FRI model by describing the curricula adapted in FRI research streams in four areas of chemistry: organic, inorganic, analytical, and biochemistry. We will show how each stream engages students in authentic research with unexpected yet potentially publishable outcomes, while also providing the necessary chemistry skill sets required for an accredited curriculum for introductory chemistry lab courses. While each chemistry stream is distinct with a specialized research focus, each satisfies the accepted American Chemical Society accreditation guidelines for teaching the required general chemistry skills shown below.1 To learn chemistry, students must directly manipulate chemicals, study their properties and reactions, and use laboratory equipment and modern laboratory instruments. Laboratory experiences should include the following activities: • Anticipating, recognizing, and responding properly to potential hazards in laboratory procedures • Keeping accurate and complete experimental records • Performing accurate quantitative measurements • Interpreting experimental results and drawing reasonable conclusions • Analyzing data statistically, assessing the reliability of experimental results, and discussing the sources of systematic and random error in experiments • Communicating effectively through oral and written reports • Planning and executing experiments through the use of appropriate chemical literature and electronic resources • Synthesizing and characterizing inorganic and organic compounds When compared to traditional laboratory courses, coursebased undergraduate experiences are known to have positive outcomes on student learning, self-efficacy, and motivation to pursue science.17 All FRI laboratories teach laboratory safety practices, notebook keeping, data analysis and interpretation,

involving relatively small numbers of students (800) into original research activities, called “streams”, as an alternative to entry-level chemistry, physics, or biology laboratory courses. FRI students participate in a three-course sequence: an interdisciplinary, inquiry-based research methods course, followed by two semesters of research in one of 30+ different research streams. During the first semester in a research stream, students earn lower-division lab credit. For the chemistry streams, the credit is the same as the introductory general chemistry lab. Students who choose to continue with the program (about 60−75%) also receive upper-division research credit. In each stream, groups of 35−40 undergraduate students work on a common research problem with mentorship and guidance from a postdoctoral-level research educator (RE), one or more university tenured or tenure-track principal investigators (PIs), a graduate student teaching assistant, and 6−10 undergraduate peer mentors. The research educator collaborates with the stream’s PI on setting the overall research goals of the stream. Research educators are responsible for designing the stream’s curriculum and ensuring that introductory experiments performed by the students prepare them for pursuing independent research. They also mentor the students in selecting individual research projects, executing the research plans, and analyzing data. Each FRI stream has a dedicated, fully equipped laboratory space (albeit some streams share space), which is managed by the research educator, and is separate from, yet integrated with, the activities of the sponsoring faculty member’s lab space. Although initially implemented and evaluated within the chemical sciences and allied disciplines, FRI is scalable within and across disciplines, and easily exportable to other research institutions. This model also provides for reform and modernization of the undergraduate curriculum, the specialized training of undergraduate B


General and Advanced Chemistry Topics

Organic synthesis; reaction mechanisms; protein−ligand interaction; binding thermodynamics; isothermal titration calorimetry Molecular interactions; protein−ligand binding; molecular modeling; binding affinities and energy minimization; mechanisms of enzyme catalysis

Buffers and ionization; noncovalent binding; molecular recognition; peptide structure and synthesis; binding affinities and dissociation constant Dissociation constants; hydrogen bonding; coordination chemistry; redox chemistry; steric interactions Coordination chemistry; synthesis of metal complexes; X-ray crystallography; photoluminescence; fluorescence spectroscopy

Discipline and Research Topic

Organic Chemistry. Understanding molecular recognition is the research focus of this stream. Students in this stream rationally design ligands by varying structural features, such as hydrophobic surface area, size, and position of electrostatic groups. After consulting the literature, they plan and execute the synthesis of their chosen ligand. They examine binding interactions of their synthesized molecules by protein crystallography and use isothermal titration calorimetry to determine the Ka, and hence ΔG°, as well as ΔH° and ΔS° for binding to a protein target. Biochemistry. Students in this stream carry out drug discovery for the treatment of infectious diseases such as tuberculosis, malaria, African sleeping sickness, typhus, leishmaniasis, and Chagas disease. Students use both computational and wet lab techniques to select and validate chemical compounds that may inhibit enzymes that are crucial to the survival and infectivity of these organisms.

Inorganic Chemistry. Research in this stream focuses on the synthesis and characterization of metal complexes, which have the potential for useful technological applications such as probes in biological systems, light-emitting diodes, and photovoltaic devices (solar cells). The metal coordination compounds contain lanthanides or rare earth metals, which can exhibit photoluminescence.

Inorganic/Analytic Chemistry. Research in this stream focuses on the synthesis and characterization of nanoparticles using combinations of metals including copper, gold, platinum, palladium, and nickel. The goal is to identify efficient chemical catalysts for medical and industrial applications.

Organic Chemistry. The goal of this stream is to mimic the mammalian sense of taste by creating sensor arrays for fingerprinting complex mixtures, a technology that has potential environmental and clinical diagnostic applications. Currently, the stream uses peptide-based sensing ensembles to differentiate red wine varietals and blends.

The participants per year by FRI stream are 35−40 undergraduates; 6−10 peer mentors; and 1 graduate teaching assistant. The Virtual Drug Screening stream has 2 senior peer mentors rather than a graduate teaching assistant. bThe instructional staffing for some of the streams presented here has changed since the manuscript was written. An updated list of faculty leaders and research educators is available on the FRI Web site: cns.utexas.edu/fri. cEric V. Anslyn is the principal investigator; Eman Ghanem is the research educator. dKeith Stevenson, David Vanden Bout, and Richard Crooks are the principal investigators; Stacia Rodenbusch is the research educator. eRichard Jones and Bradley Holliday are the principal investigators; Lauren DePue is the research educator. fStephen Martin is the principal investigator; Kristen Procko is the research educator. gJon Robertus is the principal investigator; Josh Beckham is the research educator.

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Virtual Drug Screeningg

Nanomaterials for Chemical Catalysisd Functional Materials Based on Metal Complexese Synthesis and Biological Recognitionf

Supramolecular Sensorsc

FRI Streama,b

Table 1. Description of the FRI Research Streams Featured in This Publication

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spectroscopy to characterize the peptide-based sensing ensembles as described below, students also characterize the newly synthesized peptides before they are included in the sensing array. High-performance liquid chromatography and liquid chromatography−mass spectrometry are routinely used to check for peptide purity and molecular mass, respectively. Students learn to prepare and run their samples, analyze data, and draw conclusions regarding the purity and identity of their peptides.

scientific writing, and experimental design as part of their curricula. Here, we have chosen to highlight illustrative examples of a number of chemistry subdisciplines via five FRI Research Streams, to show how each teaches the selected introductory chemistry lab skills, emphasizing the unique nature of each stream’s research: making (synthesis), measuring (UV−vis spectroscopy), and characterization. There are several examples in the chemical education literature for teaching modules that introduce the concepts of Beer’s Law,18,19 synthesis,20,21 and characterization.22,23 Traditional and inquiry-based modules are usually taught over a limited period of time, one to a few weeks. The FRI modules introduce concepts in the context of a research project. Those concepts are further reinforced and implemented by conducting independent research. For example, students in the Supramolecular Sensors stream are initially introduced to UV−vis spectroscopy through performing binding assays based on a color change. This concept is later re-emphasized and applied in a collaborative environment by conducting differential sensing research projects. This iterative model is inherent to the scientific process and will be demonstrated across research disciplines over the following sections. We also discuss how each stream manages students’ involvement and contribution to their research projects.

Using UV−Vis Spectroscopy To Determine Binding Ratios

Using the product of their solid phase peptide synthesis, students in the stream construct peptidic differential array sensors that undergo indicator displacement assays to discriminate wine varietals through supramolecular assembly (Figure 1).25 Students use UV−vis spectroscopy to determine

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FRI RESEARCH STREAMS The five FRI research streams featured in this article, The University of Texas faculty involved, and their research focuses are summarized in Table 1. The syllabi used for the introductory lab courses taught by the streams are provided in the Supporting Information. Upon completion of the introductory experiments, FRI students are engaged in collaborative, yet independent, research projects where they produce novel data. As arranged with the research educator, each student chooses the project(s) they are most interested in pursuing. Students are given the opportunity to develop the research plan for their projects, adjust conditions, and search the literature for alternative routes based on outcomes. Research educators meet regularly with the students to discuss research outcomes and advise on the next steps.

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Figure 1. Schematic representation of the indicator displacement assay used in the Supramolecular Sensors stream. Displacement of the colorimetric indicator by tannins in wine causes a color change, which is monitored spectrophotometrically.

the binding ratios of the three sensing ensemble components (colorimetric indicator, divalent metal ion, and peptide) at which the ensemble is most sensitive to the addition of tannins. Binding of tannins to the sensing ensemble causes spectral changes to the colorimetric indicator, which is monitored using UV−vis spectroscopy. In doing so, students learn the underlying theory of spectroscopy, calibration and binding isotherms, molecular recognition, and the intermolecular forces involved in the assembly of the sensing ensembles. In addition, students run high-throughput screens using 96-well plates and a plate reader to discriminate target complex mixtures. Classification is obtained using pattern recognition and principal component analyses.24,26,27

SUPRAMOLECULAR SENSORS STREAM

Peptide Synthesis

Students in this stream use solid phase peptide synthesis (SPPS) to construct short peptides as a component of metal/ peptide/indicator sensing ensembles, which are used to fingerprint red wine varietals based on their tannin composition.24 Consequently, students are introduced to different functional groups and how they react to form new products. They also learn the reaction sequence of the SPPS cycle: deprotection, coupling, and cleavage of the newly synthesized peptide from the resin. Each student is responsible for constructing a short peptide of 6−10 amino acids. In performing SPPS, students practice: (i) using a rotary evaporator to remove organic solvents from the peptide, (ii) using a lyophilizer to freeze-dry their final products, and (iii) making synthesis-related calculations such as theoretical yield and reaction efficiency.

Managing Research Projects on Developing and Optimizing Sensor Assemblies

Like any other research lab, each FRI stream has a main research goal that is achieved by executing multiple projects. Students choose which project they are interested in pursuing. For the peptide-based sensors project, each student works on developing and optimizing a sensor assembly. This involves synthesizing and characterizing peptides; testing binding affinities to divalent metals; and determining the optimum binding ratio of the metal, indicator, and peptide. The results

Peptide Characterization

Following peptide synthesis, students employ multiple characterization techniques that are traditionally taught in upper-division lab courses. In addition to using UV−vis D



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obtained from each student are collectively analyzed to determine the best sensing array for particular complex mixtures, such as wine varietals or wine blends. Once the sensors are optimized, high-throughput screens for differential sensing are performed by a team of 4−6 students since they involve collecting a large data set. For reproducibility, students may work on parallel projects. The research educator meets weekly with the students to discuss progress. In addition, students present their research findings to their peers and the principal investigator, which provides them with training in science communication. The stream’s curriculum is designed to teach the required chemical concepts in the context of the research goals. For example, buffer preparation and mechanism of action is taught as a preparatory experiment for the metal, indicator, and peptide binding assays, since they require a certain pH to ensure the correct protonation state of all components. During the first half of the spring semester, and while students are learning lab techniques, they are assigned lab times that fit their class schedule. After they begin working independently, they choose their lab time on a shared calendar. For safety practices, students are required to choose a lab time when a peer mentor is present. In most cases, laboratories are open for 8−10 h per day and on weekends. Students are responsible for preparing all materials needed for their project. As needed, they are assisted by their peer mentors. Any manuscripts created are drafted by the research educator (RE) with significant student participation. The students compile the data, generate figures, and read and edit the paper during its production. Ultimately, the principal investigator edits the paper, cycling it back and forth with the RE and students, until a final version is ready for submittal and peer review. In this manner, the students learn scientific writing and the publication process.

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Figure 2. Dendrimer-encapsulated nanoparticle-catalyzed reduction of p-nitrophenol (λ max ∼400 nm) to p-aminophenol

degradation over time using UV−vis spectroscopy.30 Students learn how to analyze reaction kinetics and determine the order of their reaction. Once students have mastered this type of characterization, they are free to vary the concentrations of the reactants to explore reaction mechanism, the type and size of nanoparticles they use as catalysts, or to test other substrates such as variously substituted nitrophenols. Using UV−Vis Spectroscopy to Explore Metal Complexation

Students in this stream are first introduced to the concept of Beer’s Law in a laboratory module in which they determine the molar absorptivity of two colored organic molecules, 2nitrophenol and 4-nitrophenol, that they will use as substrates in their catalytic reactions later in the semester. In addition, the students examine iron complex equilibria by determining the molar absorptivity and the equilibrium constant of formation for three iron complexes: monodentate (thiocyanate [SCN−]), bidentate (salicylate [C 7 H 4 O 3 2− ]), and multidentate ([EDTA4−]). This introductory experiment provides the framework for understanding the complexation of metal ions within dendrimer molecules during nanoparticle synthesis. To further explore metal complexation using spectroscopy, students perform a spectrophotometric titration of a dendrimer solution with copper ions.31 Each incremental addition of copper to dendrimer causes an increase in the 300 nm ligandto-metal-charge-transfer (LMCT) band and the d-d transition band at 605 nm.30 Students determine the binding capacity (or “loading capacity”) of the dendrimer as the inflection point of a graph of the absorbance at 300 nm versus the molar excess of copper to dendrimer,30,32 or they can apply the binding isotherm that was published by the stream.32 Students also examine the effect of altering the dendrimer pH on the loading capacity, which introduces the concept of competitive binding (of protons and metal ions for the interior amines of the dendrimer).

NANOMATERIALS FOR CHEMICAL CATALYSIS STREAM

Nanoparticle Synthesis

Students in the Nanomaterials stream synthesize Dendrimer Encapsulated Nanoparticles (DENs) as catalysts using a protocol that they write for themselves, based on previously published literature.28 They are guided through the synthesis protocol design by a series of questions and suggested calculations, using our published guide.29 DEN synthesis involves the preparation of aqueous solutions of dendrimer and metal salt, combining the dendrimer and metal salt in the appropriate ratio, complexation, and reduction with a chemical reducing agent. The reduced nanoparticles are retained within the dendrimers by steric interactions.30 The dendrimer alone, the dendrimer-metal complex, and the reduced nanoparticles, each display unique spectral profiles, and hence students can follow the progress of their synthesis using UV−vis spectroscopy as described below. Learning nanoparticle synthesis reinforces general chemistry concepts such as the dissociation of ionic compounds in solution, hydrogen bonding, metal coordination, redox chemistry, and steric interactions.

Managing Research Projects for the Nanomaterials Stream

FRI streams have two different modes of project structure that allow student involvement to scale: either each student works on a piece of a larger project, or each student works on parallel projects, with a similar structure. In the Nano stream, student projects can follow either of these modes. Some students work in parallel on nanomaterials synthesis and characterization, and others may work only on a specific aspect of a project, such as developing a new catalytic assay for particle screening. As a hybrid mode, multiple students may work in parallel attempting to develop the new assay. Project selection contributes to project ownership, and so students actively participate in this process. Before selecting a project to work on in the Nano stream, students are provided with project one-pagers that summarize background articles, progress, and remaining goals for each ongoing project in the

Nanoparticle Characterization

Students characterize the catalytic activity of their nanoparticles using model reactions that can be monitored by UV−vis spectroscopy, such as the reduction of nitrophenols (Figure 2). For example, 4-nitrophenol has a characteristic absorption peak at ∼400 nm in basic solution, making it possible to monitor its E



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new heterotrinuclear Schiff-base complexes,34 photophysical properties of samarium coordination compounds,35 lanthanide containing polymers with flexible Schiff-base ligands,36,37 and self-assembled lanthanide coordination compounds shaped like nanodrums.38

stream. They then write a brief proposal summarizing the aspect of the project that they would like to address. If the Research Educator does not see the students’ proposal as feasible, or if their proposal does not relate to the goals of the stream, they meet one-on-one with the student to come up with a project together. Once projects are underway, if a student project stalls, the Research Educator may guide the student toward a project that needs another pair of hands. Meeting consistently with the same group of people helps to build a sense of community. To build community in the Nano stream, for the first few weeks in the stream, students are assigned a lab time that fits into their schedule, and they meet consistently during this time with the same group of students and a peer mentor. This structure also makes it easier to train students together. After this initial period, students sign up themselves, with a lab safety partner, on a google calendar, and record their hours in a google form. Two elements determine the syllabi of FRI courses: first, the minimal skills required to be taught for the course credit offered, as specified by the course and curriculum committee for the department, and second, the particular skills needed for the students to be productive in and contribute to the research. With the exception of a few skills-development laboratories early in spring, students support the preparation of their own experiments. When needed, the Research Educator and peer mentors share the preparatory responsibilities.

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Characterization: Learning IR and 1H NMR Spectroscopy and Crystallization Techniques

Using scientific literature as a teaching guide, the students are taught several ways to characterize and evaluate the purity of new compounds including infrared (IR) spectroscopy and proton nuclear magnetic resonance (1H NMR) spectroscopy. They are also taught crystallization techniques including slowcooling, slow vapor diffusion, and slow evaporation in order to grow X-ray quality crystals. The crystals are used for single crystal X-ray diffraction studies (Figure 3). Students learn to screen crystals under a microscope and mount them on a diffractometer in order to collect the diffraction data. Advanced students in the stream develop the skills to solve their own crystal structures. At the end of each research semester students submit formal written accounts of their results, which are peerreviewed and graded with the option for them to resubmit to show improved writing skills, additional data and characterization, and the goal of accomplishing something that will potentially be published. UV−Vis Spectroscopy of a Nickel Diamine Compound

Students are introduced to UV−vis spectroscopy early on in their training by determining the molar absorptivity using Beer’s Law of a nickel diamine compound.39 Students find the wavelength of maximum absorbance of the compound and then by using serial dilutions record the absorbance at the maximum wavelength for each solution. Students learn how to export their data, plot the data, and discuss their results in an analytical fashion. The excited state of a ligand bound to a lanthanide is determined using UV−vis spectroscopy, and students learn this by involvement in an experiment during their first semester.33 During the following semester(s), students characterize new ligands and coordination compounds by using UV−vis spectroscopy. The luminescent emissive properties of the compounds, both in solution and the solid state, are also explored using a state-of-the-art fluorimeter.

FUNCTIONAL MATERIALS BASED ON METAL COMPLEXES STREAM

Synthesis of Lanthanide Coordination Compounds

During the first semester in this stream the students are taught how to synthesize lanthanide coordination compounds using literature procedures (Scheme 1).33 During the second Scheme 1. Synthesis of Eu(tmh)3bpy and Tb(tmh)3bpy

Managing Research Projects on Lanthanide Coordination Complexes

During the second semester in this stream, students work on independent projects, which consist of organic Schiff-base ligands that will form lanthanide coordination complexes. Each student is assigned one ligand to synthesize which is determined by the RE and the PIs. In some instances, the advanced students (FRI mentors) develop their own projects.

semester the students are grouped into projects that vary from changing the functional groups of organic ligands to developing new coordination compounds by varying solvents, reaction conditions, and crystal growing techniques. Several student projects have been published including those describing

Figure 3. Diagram showing the sequence of experiments that take place in the Functional Materials stream to characterize the complex Tb2(N,N′bis(6-bromo-3-methoxysalicylidene)phenylene-1,2-diamine): ligand synthesis and crystallization, mounting of crystals on the X-ray diffractometer, obtaining a diffraction pattern, and, last, solving the crystal structure. F



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hydrogen bonding residue in the active site. Students performed two or three synthetic steps en route to these heterocyclic molecules that are studied by isothermal titration calorimetry (ITC) for protein binding, and protein crystallography, in subsequent semesters (II−IV in Figure 4). Reactions used to form these compounds typically involve air-free chemistry, liquid−liquid extractions, and purification methods such as distillation, recrystallization, and flash chromatography.

The students master synthetic techniques, purification, and characterization by proton nuclear magnetic resonance (NMR). This is followed by a series of reactions to coordinate their ligand to lanthanide salts and form self-assembled lanthanide coordination complexes that are fully characterized by single crystal X-ray crystallography (XRD). Students learn how to collect the data for single crystals and how to solve crystal structures. Projects that are successful are grouped together by type of ligand. The papers published include all the names of the participating students. Students are not assigned laboratory time. Rather, they work independently as dictated by their projects. In this stream, responsibilities of peer mentors include preparation of common reagents, ordering supplies, and assisting students with their projects as needed. The syllabus and components of lab instruction are determined by the research goals of the group and what students need to learn in order to accomplish these goals.

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Characterization of Organic Molecules Using IR and 1H NMR Spectroscopy

The two principal characterization methods students learn during their first semester in this stream are infrared (IR) and nuclear magnetic resonance (NMR) spectroscopy. They first use these techniques to characterize the primary standard for the organometallic titration (Figure 3). Using IR spectroscopy, students find and report the wavenumbers for peaks corresponding to carbonyl and N−H stretches of their amide product. They compare these data to an IR spectrum of the starting acid chloride, noting the change in wavenumber of the carbonyl group between the starting material and product; these observations are included in a formal lab report. Students also analyze the 1H NMR data, which they acquire themselves for their product, and first assign peaks that are correlated to protons on the molecule based solely on integration. The compound contains aromatic protons that couple with each other, so students begin to learn about the origin of spin−spin splitting in NMR spectroscopy. As the students move on to their synthetic projects, they continue to develop their NMR interpretation skills, acquiring 1H NMR spectra for both crude and purified products while performing ligand syntheses. They look for characteristic peaks in spectra of crude reaction mixtures to determine if the reaction was successful. Through formal written accounts, they fully characterize purified compounds and report the spectra obtained for each synthetic step en route to their final ligands.

SYNTHESIS AND BIOLOGICAL RECOGNITION STREAM

Synthesis of Organic Molecules

This stream is focused on organic synthesis and protein−ligand interactions, which allow students the option to claim upperdivision organic lab credit in a later semester if they continue research in the stream. Students synthesize several organic molecules during the first semester. Using a published procedure, they learn to manually determine the stoichiometry of organic reactions and then use their data to modify the scale of those procedures. In their first synthetic experiment, they create a primary standard for the titration of organolithium reagents (amide I in Figure 4).40 Following an air-free organic

UV−Vis Spectroscopy of Students’ Novel Ligands

Many of the ligands synthesized in this stream are aromatic or contain at least one double bond. Accordingly, the concentration of these compounds can be determined by UV−vis spectroscopy. Accurate solution concentrations are critical for ITC experiments, and knowing the extinction coefficient of a compound in the ITC buffer allows students to calculate these concentrations effectively. Students use a Beer’s Law experiment to find the wavelength of maximum absorbance (λmax) for their novel ligand. They then create solutions of varying concentration by accurately weighing out samples of the ligand on a microbalance. After collecting absorbance data at λmax for each solution, the student calculates an extinction coefficient for the molecule, using their R2 value to evaluate whether their data fits the model well.

Figure 4. Examples of compounds synthesized by students in the Synthesis and Biological Recognition stream: an amide containing primary standard for the titration of organolithium reagents (I) and examples of heterocyclic ligands for MUP-1 (II−IV) where R = nalkyl, branched alkyl, cycloalkyl, or aryl group.

reaction, students perform liquid−liquid extraction to separate organic compounds from a salt that forms during the transformation. They then remove residual water from the organic phase using a drying agent and separate the crude product from organic solvents via rotary evaporation. Finally, they purify the compound by recrystallization and calculate a percent yield. At the end of the first semester, students perform multistep syntheses of organic compounds to create molecules for protein binding studies. The initial protein target selected for the stream, the mouse major urinary protein-I, contains a largely hydrophobic binding site that forms complexes with nonpolar ligands in an enthalpy driven process.41,42 Because this protein binds a variety of molecular scaffolds, it was a suitable target for designing a number of diverse student projects. Undergraduates employed parallel synthetic routes to create a group of structurally similar, yet distinct, heterocyclic ligands to explore binding thermodynamics and evaluate the contribution of a

Managing Research Projects for Synthetic Targets

In this stream, students are assigned lab time for early experiments involving shared equipment; however, for most experiments, students self-schedule on a group calendar. Peer mentors support the preparation of experiments by checking supplies and preparing lists of materials that the research educator has requested. Students perform most of their own lab preparation. As they begin working on independent research projects, each student determines the materials needed for their research and checks for their own supplies. Once they complete an online spreadsheet comparing prices from three main G



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In a nonconventional sense of synthesis, students in this stream perform in vivo protein synthesis in an E. coli expression system under the control of a constitutive promoter. After 16 h of protein expression, the bacterial culture is harvested, and the cell pellet is frozen with lysozyme to digest the cell walls. The cell lysate is then clarified through centrifugation to yield the soluble proteins. The target protein is then purified through nickel affinity column chromatography using an N-terminal 6× histidine tag on the synthesized protein. Initially, the same protein is synthesized and purified by each member of the class in order to develop the skills for doing so with their ultimate targets being proteins associated with the infectious disease of interest.

by examining the 3-dimensional poses of small molecules bound into X-ray crystallography protein structures that have been retrieved from the online repository.43 A molecular graphics program, PyMOL, is used to visualize the steric constraints of nearby atoms and the spatial arrangement of potential hydrogen bonds, van der Waals interactions, and hydrophobic forces.44 After developing an understanding of the binding modes of known structures has been completed, students execute virtual drug screening protocols using the molecular docking program GOLD.45 For each docking pose an overall Fitness Score and the contributing subscores are analyzed by the students to rank-order the potential ligands. A set of ligands which are known to bind the protein are used as a validation set. The placement of the heavy atoms of the docked poses for these validation ligands is compared to the known Xray crystallography poses, and the differences are reported as the RMS (root mean squared) deviations between the two. A large deviation lets the students know that the docking software did not accurately place the ligand in the known pose into the active site and, therefore, they may not have as much confidence in their results. Ideally by the end of their research projects that span through the summer and fall semesters, students will have taken their selected targets through cloning the coding DNA sequence into a plasmid vector, expressed, and then purified the protein in E. coli. Then the students will have tested several of the compounds from the virtual screening predictions through enzyme assays in the wet lab to validate the virtual results, and to provide hit compounds for further drug discovery.

Characterization of Target Proteins

UV−Vis Spectroscopy of Purified Target Proteins

After protein expression and purification, students characterize their yield through SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis). Samples that have been collected at different stages throughout the expression and purification procedure are loaded into the lanes of the gel: cell lysate, soluble fraction, flow through, wash fraction, first imidazole elution, and second elution. Through this procedure students are able to determine the size of their model protein, as well as estimate the purity based upon the presence of contaminating bands in the gel. They also estimate the yield of their expression and purification procedure by visualizing the intensity of the band on the gel relative to other bands, and then more accurately quantifying it by measuring the absorbance of the protein at 280 nm on a microvolume spectrophotometer (Nanodrop, Thermo Fisher Scientific, Wilmington, DE). Once again, the goal is to prepare the students to execute the required characterization of their target protein. Additionally, students perform an enzyme assay of a tyrosine phosphatase (EC 3.1.3.48) involved in virulence of the bacterium Yersinia pestis performed to verify whether the protein is active. While the natural substrate for the enzyme is a phosphorylated tyrosine residue, a surrogate substrate, pNPP (p-nitrophenyl phosphate), is used instead, which can be monitored easily in a cuvette-based spectrophotometric, endpoint assay. The cleavage of this substrate in basic conditions results in the formation of p-nitrophenolate, which is monitored spectrophotometrically at 410 nm. Students begin the process of target discovery by selecting plausible virtual targets from the Protein Data Bank (PDB), each of which is a potential enzyme target from infectious diseases. The students characterize protein−ligand interactions

In addition to the enzyme assays described above, students use UV−vis spectroscopy to measure the concentration of the final purified target protein. The students measure the absorbance of the protein at 280 nm on a microvolume spectrophotometer. The concentration is then measured using the calculated molar extinction coefficient based upon the amino acid sequence, which is obtained from an online database, ExPASYProtParam.46

vendors, a peer mentor reviews the sheet and submits the finalized request to the research educator for approval and ordering. In the synthesis stream, students select synthetic targets from existing unfinished projects or by designing a novel molecule. In the final activity, groups of students assist a mentor with his or her research project. The research educator assists those having difficulty selecting a compound to study by helping the students identify an interesting aspect of molecular recognition. Biochemistry-focused students work in a separate lab, expressing proteins and executing binding assays. Typically, groups of students work on one protein, handing off lengthy protocols.

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VIRTUAL DRUG SCREENING STREAM

Protein Synthesis

Managing Research Projects to Determine Protein Selection

In this stream, students work on multiple projects in parallel. Teams consist of one to four students, with one- or two-student teams being the most common. Each project focuses on a single enzyme from an infectious disease organism. For example, a project may focus on the YopH phosphatase protein from the bacterium Yersinia pestis, the causative agent of the bubonic plague. Other projects focus on reductase targets such as 3oxoacyl-ACP reductase (FabG) from the protozoan parasite Plasmodium falciparum. All of the projects share common laboratory techniques such as molecular cloning, protein expression, purification, and characterization. With the aim of providing opportunities for project ownership, students contribute to determining which proteins will be selected for their projects. In the spring semester, a Target Discovery protocol is completed by the students to first find an organism to study, which is from either a bacterial or protozoan parasite. They then select a particular enzyme, which is crucial for the survival or virulence of the infectious organism. Laboratory time usage progresses from more structured to less structured, from the spring to fall semesters. In the spring when students are learning new techniques, they are assigned a H



Article

factors that contribute to the growth and success of the program. Faculty support and buy-in are critical for program implementation at other colleges and universities. Curriculum integration is another key aspect of the FRI model. Students often perceive research as more challenging than the traditional laboratory courses. Offering required course credit to take on this challenge is a good incentive that promotes and broadens participation. Research educators are critical to the success of full scale FRI streams (35−40 student enrollment). However, several FRI streams operate at a lower capacity with enrollment size of 15−20 students. Those streams are mentored by either a graduate student or a postdoctoral researcher. In fact, many FRI streams begin as “half streams” that expand over time as more resources are made available through institutional support or external funding. The FRI model offers sustained research experiences and integrates different types of mentorship opportunities. Peer mentors are integral to the FRI experience. They guide and encourage incoming students as well as cultivate a supportive research culture within the stream. Finally, parallel projects are good for scalability. Developing similar, yet unique, projects allows the students to work together and assist each other with lab techniques while maintaining ownership of their research.

lab time each week depending on the procedure. Students schedule their own lab time based on the availability of peer mentors. The syllabus and lab components are determined primarily by the needs of the projects. Some of the spring material, which is required for chemistry lab credit, is adapted to be more directly relevant to the projects. For example, the Beer’s Law spectrophotometry lab uses an indicator dye (pnitrophenolate), which is the product of the enzymatic reaction for many of our phosphatase proteins. Students are responsible for preparing their own reagents. Over the course of their time in the stream, they learn how to make more of the materials necessary for their work such as media plates and buffers. Peer mentors may also be tasked with preparing certain reagents that are needed for the class.

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SUCCESS IN RESEARCH: PEER-REVIEWED PUBLICATIONS FRI has permanently altered the culture of our college and inspired concrete curricular change across departments. It has begun to serve as a national model to inspire other institutions to look beyond traditional barriers to large-scale undergraduate research. For example, in recognition of FRI’s groundbreaking approach to integrating research and teaching, The Howard Hughes Medical Institute has established “Adaptation of Freshman Research Initiative (FRI) Model” as one of four thematic areas supported by its $60 million initiative to improve undergraduate science education. One of the aspects that make the FRI unique and innovative is that it is mutually beneficial for students and faculty. A detailed analysis of the outcomes of FRI showed that participation in the program has a positive impact on students’ performance and increased retention in STEM majors and graduation rate.47 Importantly, FRI research streams are more than educational entities; they are productive research laboratories where undergraduates contribute to research in areas that relate directly to the ongoing research of the UT faculty. To date, over 140 FRI students have coauthored peer-reviewed published or in-press research articles. For example, students in the Supramolecular Sensors stream have coauthored six publications describing different applications of the indicator displacement assay and differential sensing in fingerprinting complex mixtures.24,26,27,48−50 The Nanomaterials for Chemical Catalysis stream has published five papers since it was founded in 2006; each of these articles includes at least two undergraduate student authors.29,32,51−53 Similarly, undergraduates in the Functional Materials Based on Metal Complexes stream have significantly contributed to scientific research as evident from their peer-reviewed publications in highly reputable journals.35−38 In addition to peer-reviewed publications, FRI students frequently present their research and win awards at national and regional conferences, such as ACS Annual National and Regional Meetings, the Annual Biomedical Research Conference for Minority Students (ABRCMS), the Gulf Coast Undergraduate Research Symposium at Rice University, and the Council on Undergraduate Research Posters on the Hill Conference.

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CONCLUSIONS

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ASSOCIATED CONTENT

The FRI program demonstrates that a variety of research topics can be used as the basis for a first-year chemistry laboratory experience, to the benefit of both students and faculty. The FRI has provided a mechanism for an early, productive integration of undergraduates in the research process. The University of Texas at Austin has implemented the FRI model on a large scale (30 research topics); smaller universities could apply the same structure to one or two research areas in order to update their curriculum and engage students in research earlier in their undergraduate careers. The key to the FRI model is teaching laboratory techniques in the context of cutting-edge research. We have shown that basic techniques such as making (synthesis), measuring (UV-vis spectroscopy), and characterization can be taught in this manner. Yet these basic skill sets also provide open-ended laboratory research experiences, ranging from synthesizing and characterizing molecules, complexes, and nanomaterials; to characterizing their behaviors using UV−vis spectroscopy; to assessing and quantifying the data toward application as molecular sensors, catalysts, and enzymatic assays. With this new model, we have demonstrated that full integration of training in mandatory accredited chemistry skill sets, with open-ended research experiences resulting in new and unexpected outcomes in undergraduate science curricula, can be achieved at a large scale with benefits to teachers, researchers, and students.

S Supporting Information *

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The Supporting Information is available on the ACS Publications website at DOI: 10.1021/acs.jchemed.7b00294.

KEY CONSIDERATIONS FOR IMPLEMENTATION AT OTHER INSTITUTIONS The Freshman Research Initiative was piloted in 2005 with 43 students enrolled in three research streams. There are several

Syllabi for the introductory general chemistry laboratory courses taught by the five FRI streams featured in this paper (PDF) I



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AUTHOR INFORMATION

Corresponding Authors

*E-mail: *E-mail: *E-mail: *E-mail: *E-mail:

[email protected] (E.G.). [email protected] (K.J.S.). [email protected] (S.M.). [email protected] (R.A.J.). [email protected] (E.V.A.).

ORCID

Eman Ghanem: 0000-0002-7024-5770 Stephen Martin: 0000-0002-4639-0695 Richard A. Jones: 0000-0003-4174-6530 Eric V. Anslyn: 0000-0002-5137-8797 Present Addresses ⊥

Eman Ghanem: Sigma Xi, The Scientific Research Honor Society, P.O. Box 13975, Research Triangle Park, North Carolina 27709, United States. ¶ Kristen Procko: University of Saint Joseph, West Hartford, Connecticut 06117, United States. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors gratefully acknowledge the financial support of the National Science Foundation (Grant CHE-0629136), the Howard Hughes Medical Institute (Grants 52005907, 52006985, and 52008124), and the W. M. Keck Foundation (Grant UTA15-000786). The Freshman Research Initiative is funded in part by the College of Natural Sciences at The University of Texas at Austin and the gifts of donors and alumni.

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Teaching through Research: Alignment of Core Chemistry

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