3 research outputs found
Computations of 36 Tautomer/Isomer Equilibria of Different Lactams
Gas-phase energies of 36 tautomer/isomer pairs of 18
six-membered
N-heterocyclic compounds were computed quantum chemically. Among the
considered B3LYP, BH&HLYP, BH&HLYP(G), and PW6B95 DFT functionals,
the latter two provide accurate tautomer/isomer pair energies with
root-mean-square deviations (rmsd) relative to experiments of 0.2
and 0.3 kcal/mol, respectively. Since only few (namely five) experimental
data are available, 15 tautomer/isomer pair energies were computed
with the very precise QCISD(T)(quadruple-ζ) method serving as
reference. Relative to this reference the PW6B95 DFT functional is
slightly superior to the BH&HLYP(G) functional, yielding an rmsd
of 0.7 and 0.8 kcal/mol, respectively. In contrast to BH&HLYP(G),
the PW6B95 DFT functional yields also accurate tautomer/isomer pair
energies if zwitterionic structures are involved. The tautomer/isomer
pair states possess different amounts of aromaticity. This is characterized
by nucleus-independent chemical shift (NICS) values. The tautomer/isomer
pair reference energies, from which the energies computed with PW6B95
are subtracted, correlate linearly with the corresponding differences
in the NICS values. This correlation is used to construct a correction
term for the pair energies computed with PW6B95, yielding tautomer/isomer
pair energies with rmsd of 0.3 kcal/mol with respect to the more CPU
time demanding QCISD(T)(quadruple-ζ) method
Exploring the Possible Role of Glu286 in C<i>c</i>O by Electrostatic Energy Computations Combined with Molecular Dynamics
Cytochrome <i>c</i> oxidase (C<i>c</i>O) is
a central enzyme in aerobic life catalyzing the conversion of molecular
oxygen to water and utilizing the chemical energy to pump protons
and establish an electrochemical gradient. Despite intense research,
it is not understood how C<i>c</i>O achieves unidirectional
proton transport and avoids short circuiting the proton pump. Within
this work, we analyzed the potential role of Glu286 as a proton valve.
We performed unconstrained MD simulations of C<i>c</i>O
with an explicit membrane for up to 80 ns. Those MD simulations revealed
that deprotonated Glu286 (Glu286-) is repelled by the negatively charged
propionic acid PRD of heme a<sub>3</sub>. Thus, it destabilizes a
potential linear chain of waters in the hydrophobic cavity connecting
Glu286 with PRD and the binuclear center (BNC). Conversely, protonated
Glu286 (Glu286H) may remain in an upward position (oriented toward
PRD) and can stabilize the connecting linear water chain in the hydrophobic
cavity. We calculated the p<i>K</i><sub>a</sub> of Glu286
under physiological conditions to be above 12, but this value decreases
to about 9 under increased water accessibility of Glu286. The latter
value is in accordance with experimental measurements. In the time
course of MD simulation, we also observed conformations where Glu286
bridges between water molecules located on both sides (the D channel
being connected to the N side and the hydrophobic cavity), which might
lead to proton backflow
Understanding Selectin Counter-Receptor Binding from Electrostatic Energy Computations and Experimental Binding Studies
Higher
organisms defend themselves against invading micro-organisms and harmful
substances with their immune system. Key players of the immune system
are the white blood cells (WBC), which in case of infection move in
an extravasation process from blood vessels toward infected tissue
promoting inflammation. This process starts with the attachment of
the WBC to the blood vessel wall, mediated by protein pair interactions
of selectins and counter-receptors (C-R). Individual selectin C-R
binding is weak and varies only moderately between the three selectin
types. Multivalency enhances such small differences, rendering selectin-binding
type specific. In this work, we study selectin C-R binding, the initial
step of extravasation. We performed electrostatic energy computations
based on the crystal structure of one selectin type co-crystallized
with the ligating part of the C-R. The agreement with measured free
energies of binding is satisfactory. Additionally, we modeled selectin
mutant structures in order to explain differences in binding of the
different selectin types. To verify our modeling procedures, surface
plasmon resonance data were measured for several mutants and compared
with computed binding affinities. Binding affinities computed with
soaked rather than co-crystallized selectin C-R structures do not
agree with measured data. Hence, these structures are inappropriate
to describe the binding mode. The analysis of selectin/C-R binding
unravels the role played by individual molecular components in the
binding event. This opens new avenues to prevent immune system malfunction,
designing drugs that can control inflammatory processes by moderating
selectin C-R binding