In this presentation I will highlight two biochemical processes that are governed by key intermolecular interactions. The first focuses on the initial enzymatic step of isoprenoid biosynthesis with the second highlighting binding and specificity of β-lactam anitbiotics. 1-deoxy-d-xylulose 5-phosphate synthase (DXS) is a thiamine diphosphate (TDP) dependent enzyme that marks the beginning of the non-mevalonate isoprenoid biosynthesis pathway. The mechanism of action for DXS is still poorly understood and begins with the formation of a thiazolium ylide ion. This TDP activation step is thought to proceed through an intramolecular deprotonation by the 4’-aminopyrimidine ring of TDP. The intramolecular deprotonation is catalyzed by the deprotonation of the 4’-amino group mediated by either a histidine residue or a water molecule found proximal. In the interest of gaining a better molecular understanding, QM/MM techniques were used to compute the reaction energy profiles of the proposed mechanisms. The results show a ∼10 kcal/mol difference in transition state energies favoring the water mediated mechanism. The molecular differences that led to this observed difference were probed further and the results will be presented.  Bacterial resistance to standard (i.e. β-lactam-based) antibiotics has become a global pandemic. One possible key to unraveling critical details is characterization of the non-covalent interactions that govern binding and specificity (DD-peptidases, antibiotic targets, versus β-lactamases, the evolutionarily derived enzymes that play a major role in resistance) and ultimately resistance as a whole. Results of a detailed computational analysis targeted at elucidating these effects will be presented. Specifically, an extended π-π network is elucidated that suggests antibacterial resistance has evolved, in part, due to stabilizing aromatic interactions. Additionally, interactions between the protein and peptidomimetic substrate are identified and characterized; revealing an interaction that may significantly contribute to β-lactam specificity. Finally, interaction information is used to suggest modifications to current β-lactam compounds that should both improve binding and specificity in DD-peptidases and their physiochemical properties.