Experimental and theoretical studies in biomolecular structure and catalysis: I.~Structural studies of Lewis(a) and Lewis(x) carbohydrates using NMR and molecular modeling. II.~ab initio and hybrid density functional quantum computations of biochemical systems.

摘要

Modern computation is now sufficiently powerful to enable the meaningful study of relationships between electronic structure and biological function. Three sets of biochemical problems were approached using ab initio and hybrid density functional methods.; Phosphodiester hydrolysis is essential to life for its role in metabolism and the management of genetic information, but the details of its chemical mechanism are incompletely characterized. To probe the role of the 2{dollar}spprime{dollar}-hydroxyl group of ribonucleic acid in its hydrolysis, Dantzman synthesized 2{dollar}spprime{dollar}-thiol nucleotide analogs and compared their reactivity patterns with 2{dollar}spprime{dollar}-alcohol derivatives. Her findings inspired a series of ab initio computations to learn more about phosphodiester and phosphorothioate hydrolysis. We have constructed models of dimethylphosphate, ethylenephosphate, a tetrahydrofuran-based analog of a 2{dollar}spprime{dollar},3{dollar}spprime{dollar}-cyclic nucleoside, and their O,S-phosphorothioate equivalents, and modeled their reactions with hydroxide ion and water. Our analysis includes complete description of the intrinsic reaction coordinates, natural bond orbital analysis, bond order estimates, and prediction of kinetic isotope effects. In accord with similar investigations, we find that solvation and strain are important factors in these reactions. Furthermore, comparison of the phosphorothioate and phosphodiester systems shows stereoelectronic effects and strain to be more important than previously acknowledged.; Oxanorbornene is less reactive than norbornene in ring-opening metathesis polymerization syntheses of multivalent inhibitors of cell adhesion. To elucidate the nature of this difference, we conducted a series of ab initio calculations. Strain and electronegative inductive effects, though significant, were not sufficiently different between the systems to distinguish between them. Natural bond orbital analysis suggests that hyperconjugative delocalizations of the olefin pi-bond into neighboring antibonds are primarily responsible for the effect.; The glutamate-specific protease of Streptomyces griseus employs a unique triad of linearly-arranged histidine side chains for hydrogen-bonding to its substrate. To assess the extent to which electronic cooperativity between the three imidazole rings strengthens this H-bond, we conducted ab initio calculations on formate and formic acid complexed with one, two, and three imidazoles, and analyzed their electronic structures. Though there is evidence for significant cooperativity in this system, calculations using more sophisticated theory must be performed to make meaningful conclusions regarding this system.