Multi-scale Simulations of Bronic Acids in Prteasome Inhibition and Saccharide

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The candidate earned a Ph.D. in chemistry from the University of Georgia working under the direction of Henry F. Schaefer, Graham-Perdue Professor of Chemistry. Research performed during graduate school focused on the application of quantum mechanical (QM) methods to determine thermodynamic, spectroscopic, and structural properties of silicon and aluminum complexes. This graduate work led to the identification of highly accurate methods for use in specific molecular systems and has continued through post-doctoral training. The candidate's post-doctoral work has further extended his expertise in QM computations to boron containing molecules that rely on specific approaches due to their unique chemistry. The proposed computations will build on the candidate's background in QM methodology and provide new experience in methods to study larger macromolecules. The Research Plan will investigate the chemistry governing boronic acid (BA) based proteasome inhibition and saccharide sensing. Boronic acids have emerged as important chemical structures for use in a number of potential medical and biological applications. Chemical interactions related to these fields will be studied with the following: Mixed Quantum Mechanical/Molecular Mechanical (QM/MM) methods and mathematical modeling of reaction pathways accessed via the new Multi-Scale interface implemented in the CHARMM software suite of programs. These methods represent a new field of study for the candidate and will broaden his expertise significantly. Specifically, these computations will investigate BA based inhibition of proteasomes. Despite their promise in the treatment of a myriad of cancers, this inhibitory effect is not fully understood. Furthermore, there is an increase in chemoresistance of the only FDA approved proteasome inhibitor, Bortezoniib (a dipeptidyl-boronic acid). Determining the cause of this increased resistance and the chemical interactions of BAs in the binding pocket will provide valuable insight for future proteasome inhibitors. Three possible reasons for this resistance will be explored. These include: (1) understanding the chemical reactions for the metabolism of bortezomib, (2) adverse reactions through conjugation therapy from supplements that oxidize bortezomib, and (3) the potential inhibition of glutathionyl spermidine synthase that may potentially cause an increase in glutathione, a known target of resistance suppressing conjugates. Boronic acids have also been shown to be excellent synthetic fluorescent markers for saccharides. This proposal also plans to use QM/MM methods to understand the chemical interactions of boronic acid-sugar complexes in an attempt to develop saccharide specific sensors in a modular fashion. Results will be used to design synthetic receptors for the identification of sugar units in glycans that are representative of disease states. The Career Development Award will aid the candidate in mastering the necessary tools for these studies through continued training in the Laboratory of Computational Biology within the NlH/NHLBl. Previous postdoctoral research focused on highly accurate computation of chemical properties of smaller boronic acid model systems using QM only approaches. This award will facilitate a transition into multiple length scale (Multi- Scale) QM/MM modeling using reaction pathway techniques not currently in the candidate's repertoire. Multi- Scale simulations represent a highly significant, new area of study that bridge many computational disciplines. This award will help to establish the candidate as a leader in this new field. Additional practical experience will include the ability to modify, through computer programming, the complex computer program CHARMM. In addition to being a comprehensive biological modeling platform, CHARMM also serves as a repository for the newest algorithms in the field of computational biology and chemistry. The candidate will gain valuable experience by refining and advancing reaction path methodology during the award period. In addition to research training, further education during the award period will consist of attending grant-writing workshops and biology focused classes offered through the Office of Intramural Training and Education (OITE) at the NIH. The candidates Advisory Committee will meet annually to discuss progress and to ensure that the proposed goals are met, making recommendations where needed. Weekly meetings with the candidate's mentor will also be invaluable. This support will keep the candidate on track to successfully transition to an independent research position.