Restricting the ? Torsion Angle Has Stereoelectronic Consequences on a Scissile Bond: An Electronic Structure Analysis.

ABSTRACT: Protein motion is intimately linked to enzymatic catalysis, yet the stereoelectronic changes that accompany different conformational states of a substrate are poorly defined. Here we investigate the relationship between conformation and stereoelectronic effects of a scissile amide bond. Structural studies have revealed that the C-terminal glycine of ubiquitin and ubiquitin-like proteins adopts a syn (? ? 0°) or gauche (? ? ±60°) conformation upon interacting with deubiquitinases/ubiquitin-like proteases. We used hybrid density functional theory and natural bond orbital analysis to understand how the stereoelectronic effects of the scissile bond change as a function of ? and ? torsion angles. This led to the discovery that when ? is between 30° and -30° the scissile bond becomes geometrically and electronically deformed. Geometric distortion occurs through pyramidalization of the carbonyl carbon and amide nitrogen. Electronic distortion is manifested by a decrease in the strength of the donor-acceptor interaction between the amide nitrogen and antibonding orbital (?*) of the carbonyl. Concomitant with the reduction in nN ? ?* delocalization energy, the sp(2) hybrid orbital of the carbonyl carbon becomes richer in p-character, suggesting the syn configuration causes the carbonyl carbon hybrid orbitals to adopt a geometry reminiscent of a tetrahedral-like intermediate. Our work reveals important insights into the role of substrate conformation in activating the reactive carbonyl of a scissile bond. These findings have implications for designing potent active site inhibitors based on the concept of transition state analogues.

SUBMITTER: Strieter ER 

PROVIDER: S-EPMC4820058 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature