The 2009 Pingry S.M.A.R.T. Team (Students Modeling A Research Topic) has been working with Ann Stock of the Center for Advanced Biotechnology and Medicine at UMDNJ ‐ R .W. Johnson Medical School to design and produce accurate, physical models of transcription factors activated via histidine kinase two‐component signal transduction signaling pathways using rapid prototyping (RP) technology. Two‐component signal transduction, based on phosphotransfer between a histidine protein kinase and response regulator protein, is the most prevalent multi‐step signaling strategy in bacteria. The project focused on the conserved regulatory and effector domains in response regulator proteins and the conformational changes that accompany phosphorylation‐induced activation. Discussions with the Stock lab allowed students, using RP‐RasMol to design models of E. coli PhoB and M. tuberculosis MtrA to highlight structural and functional characteristics. The physical models which serve as "communication tools" used to enhance the understanding and applications among the scientific community. Contributing this tool to the Stock laboratory, the students have had unique opportunity to experience and participate in the activities of a research laboratory. Work is supported by grant awarded to T.Herman by the NIH NCRR SEPA and HHMI.

Pingry School's 2012 S.M.A.R.T (Students Modeling A Research Topic) Team with Eddy Arnold from The Center for Advanced Biotechnology and Medicine (CABM) at Rutgers University who utilized X‐ray crystallography to determine the structure of HIV‐1 reverse transcriptase (HIV‐1 RT) in multiple functional states which led to detailed understanding of multiple nucleoside RT inhibitors (NRTIs) and and the design of non‐nucleoside RT inhibitors (NNRTIs), including two anti‐AIDS drugs. NRTIs inhibit RT by attaching to the dNTP substrate‐binding pocket, while NNRTIs are allosteric inhibitors. Our project models the NRTI and NNRTI inhibition sites on HIV‐1 RT and demonstrates the efficacy of NRTIs in comparison to NNRTIs on various mutations of HIV‐1 RT. Our physical models contrast the binding of NRTIs and NNRTIs to RT. Specifically, we examine the NRTI drug, AZT, and the NNRTI drugs, etravirine and rilpivirine. The latter two have strategic flexibility and their structures “wiggle and jiggle” inside the binding pocket, consequently making it more difficult for a mutated RT to evade resistance. The Pingry S.M.A.R.T. Team used the findings as a basis for the design of a set of three 3‐dimensional models using Jmol and a 3‐dimensional printer to demonstrate the drug‐RT interactions. These models show interactions that reflect the current research of HIV‐1 RT inhibition. Supported by a grant from the NIH‐SEPA.

The 2010 Pingry School S.M.A.R.T. Team (Students Modeling A Research Topic) has been working with the Banta laboratory at Columbia University to design and produce accurate, three‐dimensional physical models of alcohol dehydrogenase AdhD and other enzymes with applications for use in a biofuel cell. Features being engineered into these enzymes include (1) self‐assembly into hydrogels, (2) alternate cofactor use, and (3) broader substrate specificity. Discussions with the Banta laboratory allowed the students to use RP‐RasMol to design models of enzymes studied in the lab to highlight their structural and functional characteristics. These designs were used to direct rapid prototyping machines to build physical models of these enzymes. Along with Jmol tutorials created on the Team website (www.pingrysmartteam.com) and in Proteopedia (www.proteopedia.org), these physical models serve as “communication tools” used to enhance the understanding of these enzymes and their applications among the scientific and academic community. By contributing this new tool to the Banta laboratory research team, the students have the unique opportunity to experience and participate in the activities of a research laboratory. This work is supported by a grant awarded to Tim Herman by the NIH NCRR SEPA program and the HHMI Precollege Science Education Program.

The Pingry School's 2010–2011 S.M.A.R.T. (Students Modeling A Research Topic) Team worked with Abba E. Leffler and Willy Wriggers of D.E. Shaw Research (DESRES) to explore the phenomenon of protein folding. Researchers at DESRES utilized molecular dynamics (MD) in combination with the Anton supercomputer to generate simulations of the fastest folding WW domain reported to date, FiP35 (Shaw et al. 2010). Anton's ability to predict trajectories of the atoms that constitute a protein molecule resulted in the discovery of FiP35's tendency to follow a sequential, well‐defined folding pathway. The Pingry S.M.A.R.T. Team used these findings as a basis for the design of a series of 3‐dimensional models, created with Jmol and a rapid prototyping 3‐dimensional printer, which collectively describe the protein's tendency to fold from its high‐energy, denatured state to its low energy, folded state (native conformation) according to a predictable pathway. The team also organized a corresponding Proteopedia article with embedded Jmol applets and information on the FiP35 folding pathway. This level of visualization enabled by MD simulations assists in understanding the structural basis of protein folding. The Pingry School S.M.A.R.T. Team coordinates with Tim Herman and Shannon Colton of the Center for Biomolecular Modeling at the Milwaukee School of Engineering, which receives funding from NIH‐NCRR‐SEPA.