Hopping sugars: molecular mechanism of protonated glycans rearrangement Mateusz Marianski Abstract Carbohydrates, one of the three important classes of biopolymers, are involved in a range of biological processes. Their multiple functions are facilitated by a high diver- sity and adaptability of the glycan's molecular structure which, effectively, constitutes a major challenge for glycoanalitic methods. The analysis by mass-spectroscopy (MS) methods is often complicated by glycan rearrangements for which the molecu- lar mechanism remains undetermined. In order to analyze structural prerequisites and determine the molecular mech- anism underpinning the rearrangement, I will design streamlined sampling protocol that is able to screen both conformational (within one topology) and structural (be- tween varying ion topologies) space. The density-functional theory methods are able to link a glycan sequence and 3-dimensional structure of charged glycans, are able to predict thermodynamically stable rearrangement products and propose tentative molecular mechanism. The sampling protocol will be next applied to set of oligosaccharides for which glycan rearrangements, following different mechanism, has been observed. The gly- cans include fucose migration in small Lewis A and Y antigens and their sialylated forms, and larger biantennary N-glycan. Moreover, the structural space of these gly- cans, including alternative epimers, will be explored to quantify structural prerequi- sites governing the mechanism. The proposed tentative reaction mechanism will be tested in tandem MS experiments with collaboration with Dr. Lin at Boston University Medical School. The proposal suggest a paradigm shift from explanatory to exploratory role of the- oretical methods in describing the glycans. In effect, comprehensive understanding of glycans structural space will shed lights on occurrence of multiple conformational ensembles in ion-mobility spectrometry and will help to predict and red-?ag erroneous peaks in gas-phase based glycoanalysis. 1
Statement: Although glycans play numerous roles in living organisms, e. g. provide initial hand-shake in molec- ular recognition in cell-cell communication or underpin immune system and fertilization process, deter- mination of their diverse molecular structures remains challenging for experimental methods. In the proposal, I employ quantum chemistry methods to understand a problem of internal reorganization of carbohydrates occurring during glycoanalysis to facilitate the structure assignment process using mas- spectroscopy methods. The successful project results in better structural understanding of aberrant glycosylation patterns associated with many diseases.