2 research outputs found
The carbonyl-lock mechanism underlying non-aromatic fluorescence in biological matter
Challenging the basis of our chemical intuition, recent experimental evidence reveals the presence of a new type of intrinsic fluorescence in biomolecules that exists even in the absence of aromatic or electronically conjugated chemical compounds. The origin of this phenomenon has remained elusive so far. In the present study, we identify a mechanism underlying this new type of fluorescence in different biological aggregates. By employing non-adiabatic ab initio molecular dynamics simulations combined with a data-driven approach, we characterize the typical ultrafast non-radiative relaxation pathways active in non-fluorescent peptides. We show that the key vibrational mode for the non-radiative decay towards the ground state is the carbonyl elongation. Non-aromatic fluorescence appears to emerge from blocking this mode with strong local interactions such as hydrogen bonds. While we cannot rule out the existence of alternative non-aromatic fluorescence mechanisms in other systems, we demonstrate that this carbonyl-lock mechanism for trapping the excited state leads to the fluorescence yield increase observed experimentally, and set the stage for design principles to realize novel non-invasive biocompatible probes with applications in bioimaging, sensing, and biophotonics.Recent experimental evidence shows a new type of intrinsic fluorescence in biomolecules void of aromatic chemical compounds whose origin is unclear. Here, the authors use non-adiabatic AIMD simulations to show a potential carbonyl-lock mechanism originating this phenomenon
Theoretical Insights into the Reaction and Inhibition Mechanism of Metal-Independent Retaining Glycosyltransferase Responsible for Mycothiol Biosynthesis
Understanding
enzymatic reactions with atomic resolution has proven
in recent years to be of tremendous interest for biochemical research,
and thus, the use of QM/MM methods for the study of reaction mechanisms
is experiencing a continuous growth. Glycosyltransferases (GTs) catalyze
the formation of glycosidic bonds, and are important for many biotechnological
purposes, including drug targeting. Their reaction product may result
with only one of the two possible stereochemical outcomes for the
reacting anomeric center, and therefore, they are classified as either
inverting or retaining GTs. While the inverting GT reaction mechanism
has been widely studied, the retaining GT mechanism has always been
controversial and several questions remain open to this day. In this
work, we take advantage of our recent GPU implementation of a pure
QM(DFT-PBE)/MM approach to explore the reaction and inhibition mechanism
of MshA, a key retaining GT responsible for the first step of mycothiol
biosynthesis, a low weight thiol compound found in pathogens like <i>Mycobacterium tuberculosis</i> that is essential for its survival
under oxidative stress conditions. Our results show that the reaction
proceeds via a front-side S<sub>N</sub>i-like concerted reaction mechanism
(D<sub>N</sub>A<sub>N</sub> in IUPAC nomenclature) and has a 17.5
kcal/mol free energy barrier, which is in remarkable agreement with
experimental data. Detailed analysis shows that the key reaction step
is the diphosphate leaving group dissociation, leading to an oxocarbenium-ion-like
transition state. In contrast, fluorinated substrate analogues increase
the reaction barrier significantly, rendering the enzyme effectively
inactive. Detailed analysis of the electronic structure along the
reaction suggests that this particular inhibition mechanism is associated
with fluorine’s high electronegative nature, which hinders
phosphate release and proper stabilization of the transition state