Brian R. Linton

Assistant Professor of Chemistry and Biochemistry

Phone (207) 725-3616
Title Assistant Professor
Department CHEMISTRY
Work Location 46 Cleaveland Hall
E-Mail blinton@bowdoin.edu

Research Interests
Publications

Biographical
 In 1991 Prof Linton received a B.A. in Music and Chemistry from Allegheny College, Meadville, PA. He then moved to the University of Pittsburgh, where he worked with Andrew D. Hamilton on the design and synthesis of artificial receptors, earning a Ph.D. in Organic Chemistry in 1997. This was followed by a foray into structural and molecular biology with Alanna Schepartz at Yale University, where he was an Anna Fuller Post-doctoral Fellow. His research interests focus on the intersection of organic and biological chemistry, and provide opportunities for both Chemistry and Biochemistry majors. These interests include the design of small organic molecules used to manipulate biological macromolecules, protein mimetics, molecular recognition, and receptor-mediated chemical synthesis.

Research Interests
 Professor Linton's research interests focus on understanding the interactions between molecules, and exploiting these interactions to effect chemical or biological changes. Specific areas of interest are receptor design, recognition of proteins and DNA, protein mimetics, and receptor-mediated chemical synthesis.

At the current time there are three projects underway in the Linton lab, artificial beta-sheet peptidomimetics, using hydrogen/deuterium exchange to quantify hydrogen bonding, and receptor-mediated chemical synthesis.

Beta-sheets are a fundamental secondary structure found in a variety of proteins, but are difficult to mimic in small molecules. Our approach creates small molecules which constrain peptide sidechains into the extended conformation of a beta-sheet. One straight-forward example can be found in Organic Letters, where a cystine linker to propagate an extended conformation in what is likely the world's smallest folded beta-sheet.  The rigidity of these structures permits the application to the study of various proteins whose function is derived from a beta-sheet structure, including the inhibition of HIV protease, and Ras oncogenic pathways. Additionally these structures may find uses as novel materials as well as the recognition of specific peptide sequences.  This work is supported by an award from Research Corporation.

In the course of the creation of artificial beta-sheets, hydrogen/deuterium (H/D) exchange was used to probe the hydrogen bonding charateristics.  The work in our group has shown that this technique can provide more detailed information about hydrogen bond strength than other existing methods. We have observed a novel phenomenon where H/D exchange can be used to identify the individual hydrogen bond donors and acceptors, which is difficult using other techniques.  This work recently appeared in the Journal of the American Chemical Society.  We continue to expand the usefullness of this technique by quantifying these interactions and probing the steric and electronic limitations.

A third research area relates to the exploitation of small-molecule receptors to modulate the reactivity of bound substrates. These receptors can include commercially available molecules, artificially synthesized receptors and in some cases proteins. This strategy uses binding energies to regulate the environment in which a molecule reacts, permitting control of product distribution, asymmetric synthesis, and providing models for enzyme active sites.  As part of a collaboration with Scott J. Miller, we have shown that pentapeptides can be used an asymmetric organocatalysts in the Michael addition of nitroalkanes.  They achieve this remarkable selectivity using only hydrogen bonds in the peptide backbone and sidechains.  This work is suported by the American Chemical Society - Petroleum Research Fund.

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Publications
"Deuterium exchange as an indicator of hydrogen bond donors and acceptors," Lauren R. Steffel, Timothy J. Cashman, Michael H. Reutershan, Brian R. Linton, Journal of the American Chemical Society, 2007, 129, 12956.

"Beta-sheet hydrogen bonding patterns in cystine peptides," Timothy J. Cashman, Brian R. Linton, Organic Letters, 2007, 9, 5457.

"Asymmetric Michael addition of alpha-nitro-ketones using catalytic peptides," Brian R. Linton, Michael H. Reutershan, Christopher, M. Aderman, Elizabeth A. Richardson, Kristen R. Brownell, Charles W. Ashley, Catherine A. Evans, Scott J. Miller, Tetrahedron Letters, 2007, 48, 1993.

"Thermodynamic Aspects of Dicarboxylate Recognition by Simple Artificial Receptors," Brian R. Linton, M. Scott Goodman, Erkang Fan, Scott A. van Arman and Andrew D. Hamilton, Journal of  Organic Chemistry, 2001, 66, 7313.

"An Efficient One-Pot Synthesis of 1,3-Multisubstituted Guanidines from Carbamoyl Isothiocyanates," Brian R. Linton, Andrew J. Carr, Brendan P. Orner and Andrew D. Hamilton, Journal of  Organic Chemistry, 2000, 65, 1566.

"Nitronate Anion Recognition and Modulation of Ambident Reactivity by Hydrogen Bonding Receptors," Brian R. Linton, M. Scott Goodman, and Andrew D. Hamilton, Chemistry a European Journal, 2000, 6, 2449.

"Controlling Hydrogen Bonding: from Molecular Recognition to Organogelation," Rosa E, Melendez, Andrew J. Carr, Brian R. Linton and Andrew D. Hamilton, Structure and Bonding Vol 96 - Self-Assembled Molecular Systems: Organic Versus Inorganic Approaches, Springer-Verlag: New York, 1999.

"Calorimetric Investigation of Guanidinium-Carboxylate Interactions," Brian Linton and Andrew D. Hamilton, Tetrahedron, 1999, 55, 6027.

"Host-guest Chemistry: Combinatorial Receptors," Brian Linton, Andrew D. Hamilton, Current Opinion in Chemical Biology, 1999, 3, 307.

"Orientational Dynamics of Beta-Cyclodextrin Inclusion Complexes," Natalie Balabai, Brian Linton, Adrian Napper, Satayam Priyadarshy, Alexander P. Sukharevsky, and David H. Waldeck, Journal of Physical Chemistry B, 1998, 102, 9617.

"Experimental Measurements of Low Frequency Intermolecular Host-Guest Dynamics", Alexander P. Sukharevsky, Ian Read, Brian Linton, Andrew D. Hamilton, and David H. Waldeck. Journal of Physical Chemistry B, 1998, 102, 5394.

"Electrochemical Studies on Molecular Recognition of Anions: Complex Formation Between para-Xylylene-Diimidazolinium and Dicarboxylates in Nitrobenzene and Water," Yuanhua Shao, Brian Linton, Andrew D. Hamilton, and Stephen G. Weber, Journal of Electroanalytical Chemistry and Interfacial Electrochemistry, 1997, 441, 33.

"Formation of Artificial Receptors by Metal Templated Self-Assembly," Brian Linton and Andrew D. Hamilton. Chemical Reviews, 1997, 97, 1669.

"Receptors that Assemble Themselves," Brian Linton, and Andrew D. Hamilton, CHEMTECH, July 1997, 27, 34.

"Self-Assembly as a Strategy for Artificial Receptor Design," Brian Linton, M. Scott Goodman, and Andrew D. Hamilton, Self-Assembly in Synthetic Chemistry, J. Wuest; ed., 1996.

"A Combinatorial Library Approach to Artificial Receptor Design," M. Scott Goodman, Vrej Jubian, Brian Linton, and Andrew D. Hamilton, Journal of the American Chemical Society, 1995, 117, 11610.

Funding

"Hydrogen bonding peptides as asymmetric organocatalysts," Brian R. Linton, American Chemical Society - Petroleum Research Fund, 2008-2010, $60,000 total costs.

 “Organic Scaffolds That Promote Extended Peptide Structure Through Interstrand Hydrogen Bonding”  Brian R. Linton, Research Corporation Cottrell College Science Award, 2002, $33,100 total costs.

“Acquisition of a MALDI/FT-ICR Mass Spectrometer for Multidisciplinary Research”  National Science Foundation-Major Research Instrumentation Program,   PI Elizabeth A. Stemmler, and Co-PIs Ronald L. Christensen, Brian R. Linton and Caryn K. Prudente, 2001,  $280,530 total costs.