Dr. Adediran and co-authors Michael J. Morrison and R.F. Pratt have published a paper in Biochimica et Biophysica Acta (BBA) – Proteins and Proteomics. The title is “Detection of an Enzyme Isomechamism by Means of the Kinetics of Covalent Inhibition.”

The full text of the paper can be found at: https://www.sciencedirect.com/science/article/abs/pii/S157096392100087X

Colin Smith, Professor of Chemistry

The Smith Lab studies protein structure and dynamics using a combination of computer simulation and nuclear magnetic resonance (NMR) spectroscopy. They are particularly interested in optimizing the dynamics of computationally designed proteins and understanding how mutations allosterically affect the functions of natural proteins.

To advance the understanding of atomic-level mechanisms behind critical protein functions like enzyme catalysis and allosteric regulation, it is important to first elucidate a true representation of the protein in solution. In an effort to achieve this long term goal, Dr. Smith will use the recently developed Kinetic Ensemble approach to transform the way in which nuclear magnetic resonance (NMR) data is computationally modeled to solve protein structures and measure protein motions. NMR is one of the most powerful techniques for elucidating the structure and dynamics of proteins. It enables their study in solution (unlike X-ray crystallography) and can capture critical structural rearrangements as they happen at room temperature (unlike cryo-electron microscopy). However, despite these advantages, there have been relatively few practical improvements to one of the foundational aspects behind the way protein structures are solved, namely the calculation of interatomic distances from nuclear Overhauser effect (NOE) experiments. Such methods have remained largely qualitative, resulting in large uncertainties in the atomic positions for most NMR structures. Also, the field has almost completely ignored how angular motion and kinetics affect the NOE, resulting in atoms appearing much further away from one another than they actually are. To overcome these significant deficiencies, Dr. Smith and his team will implement and test new Kinetic Ensemble-based refinement algorithms that are considerably more accurate and physically realistic than previous approaches, accounting for both angular motion and kinetics. To eliminate a significant fraction of the systematic and random structural errors resulting from poorly quantified NMR spectra, they will also integrate advances made by the FitNMR peak quantification software recently developed by their lab. These methods will be used to create better experimental NMR structures, more exhaustive models of side chain dynamics, and determine differences between solution and crystal states with unprecedented detail. This work will allow much more accurate determination of the structural dynamics in parts of the protein exhibiting significant fluctuations, including protein active sites, regulatory regions, and hidden binding sites. Such knowledge will advance our fundamental understanding of protein biophysics and facilitate rational design of new therapeutics.

Funding for this R15 Grant is provided by National Institute of General Medical Sciences (NIGMS).

Northrop’s proposal, titled “Phenazine chemistry as a means of assembling multifunctional π-conjugated organic materials” is motivated by the desire to understand how the structure, functionality, and dimensionality of π-conjugated organic materials impacts their physical, optical, redox, and electronic properties. Toward this fundamental goal he and his students will use the condensation reactions between ortho-phenylenediamine derivatives with ortho-quinone compounds to prepare multifunctional phenazine derivatives. Phenazines are example N-heteroacenes that, similar to their hydrocarbon acene analogues, exhibit desirable electronic and optoelectronic properties. Phenazines, however, are more stable, better electron acceptors (n-type materials), and more synthetically modular. The majority of phenazine derivatives synthesized to date have been linearly functionalized azaacenes while very few examples of organic materials combining phenazine and other π-conjugated functionalities are known. Developing a thorough understanding of phenazine assembly and integration into multifunctional molecules will lead to entirely new classes of organic electronic materials and significantly advance our ability to investigate fundamental relationships between size, functionality, lattice topology, and dimensionality on the properties of π-conjugated materials. The principle objectives of the proposed research are to: (1) combine experimental synthesis and first principles calculations to investigate the formation and aromaticity of simple phenazine derivatives as well as the impact of functional groups on the favorability and reversibility of phenazine condensation reactions; (2) synthesize a library of o-phenylenediamine and o-quinone functionalized building blocks that will be used in the controlled assembly of one-dimensional multifunctional phenazine derivatives and oligomers; (3) apply new knowledge from fundamental and one-dimensional phenazine studies to prepare monodisperse, two-dimensional phenazine ladders and grids. The phenazine-based multifunctional materials are expected to have unique semiconducting and optoelectronic properties with potential applications as organic field-effect transistors, photovoltaics, light-emitting diodes, and sensors.