bi5b00845_si_002.xlsx (149.89 kB)
Restricting the ψ Torsion Angle Has Stereoelectronic Consequences on a Scissile Bond: An Electronic Structure Analysis
dataset
posted on 2015-09-22, 00:00 authored by Eric R. Strieter, Trisha L. AndrewProtein
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 (ψ ∼ 0°) or gauche (ψ ∼
±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 φ and ψ torsion
angles. This led to the discovery that when ψ 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 (π*)
of the carbonyl. Concomitant with the reduction in nN →
π* delocalization energy, the sp2 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.