Research
Research
Faculty Research
Brian Linton
Research Projects
Professor Linton's research interests focus on understanding the interactions between molecules, and exploiting these interactions to effect chemical or biological changes. These intermolecular forces can include hydrogen bonding, hydrophobic forces, metal binding or electrostatic attractions. 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 two projects underway in the Linton lab, artificial beta-sheet peptidomimetics and receptor-mediated chemical synthesis.
Beta-sheet Peptidomimetics : Proteins are comprised of individual units of secondary structure (such as alpha-helices and beta-sheets) folded into a globular protein. Each type of secondary structure has a unique three-dimensional appearance. Alpha-helices twist back upon themselves to form a corkscrew shape. Beta-sheets contain several protein strands held in a linear extended conformation, with hydrogen bonds existing between adjacent strands.
Proteins are large molecules which can be difficult to synthesize. Another way to study how proteins function is to create small molecules that mimic the shape and functionality of a protein, but can be easily synthesized in the laboratory. These peptidomimetics can help us understand the mechanisms of protein action and in some cases replace a large protein in a biological interaction. Peptidomimetics must position functionality in the right orientation, but must also maintain rigidity without the assistance of the entire globular protein.
Our approach creates small molecules through organic synthesis which constrain peptide sidechains into the extended conformation of a beta-sheet. These templates rigidly hold the peptide strands in such as way as to promote the formation of hydrogen bonds between adjacent strands. This array of hydrogen bonding mimics that found in a native beta-sheet within the context of a protein.
A variety of uses can be envisioned for these peptidomimetics. The elementary forces that cause a protein to adopt a certain secondary structure can be investigated using small, easily constructed molecules. Such peptidomimetics can be applied to the study of various proteins whose function is derived from a beta-sheet structure, including the inhibition of HIV protease, Ras oncogenic pathways, and the accumulation of beta-sheet proteins found in Alzheimer's disease. Additionally these structures may find uses as novel materials as well as the recognition of specific peptide sequences.
Receptor-mediated Chemical Synthesis : Chemical reactions are controlled by a variety of electrostatic and steric factors. For two molecules to come together and react, the interacting orbitals must be able to align appropriately, without other atoms being in the way. In addition to the reactants themselves, other factors such as solvent and temperature can be used to regulate chemical reactivity.
Another approach is to use a receptor to bind to a substrate, and change its chemical reactivity. This is the approach taken by nature, where enzymes bind to a substrate, then catalyze a reaction. This can be accomplished without large proteins by creating small-molecule receptors capable of binding to a substrate, then affecting its reactivity. Our lab is currently creating receptors which rely on hydrogen-bonding and metal complexation to bind to other molecules and change aspects of the regio- and stereochemistry. If we can control the environment around a reactive atom we can control of product distribution, asymmetric synthesis, and provide models for enzyme active sites.
Beta Sheet ProjectPeptide Catalysis Project