2 research outputs found
Accelerating All-Atom MD Simulations of Lipids Using a Modified Virtual-Sites Technique
We present two new implementations
of the virtual sites technique
which completely suppresses the degrees of freedom of the hydrogen
atoms in a lipid bilayer allowing for an increased time step of 5
fs in all-atom simulations of the CHARMM36 force field. One of our
approaches uses the derivation of the virtual sites used in GROMACS
while the other uses a new definition of the virtual sites of the
CH2 groups. Our methods is tested on a DPPC (no unsaturated chain),
a POPC (one unsaturated chain), and a DOPC (two unsaturated chains)
lipid bilayers. We calculate various physical properties of the membrane
of our simulations with and without virtual sites and explain the
differences and similarity observed. The best agreements are obtained
for the GROMACS original virtual sites on the DOPC bilayer where we
get an area per lipid of 67.3 ± 0.3 Å<sup>2</sup> without
virtual sites and 67.6 ± 0.3 Å<sup>2</sup> with virtual
sites. In conclusion the virtual-sites technique on lipid membranes
is a powerful simulation tool, but it should be used with care. The
procedure can be applied to other force fields and lipids in a straightforward
manner
Molecular Mechanism of Na<sup>+</sup>,K<sup>+</sup>‑ATPase Malfunction in Mutations Characteristic of Adrenal Hypertension
Mutations within ion-transporting
proteins may severely affect
their ability to traffic ions properly and thus perturb the delicate
balance of ion gradients. Somatic gain-of-function mutations of the
Na<sup>+</sup>,K<sup>+</sup>-ATPase α1-subunit have been found
in aldosterone-producing adenomas that are among the causes of hypertension.
We used molecular dynamics simulations to investigate the structural
consequences of these mutations, namely, Leu97 substitution by Arg
(L97R), Val325 substitution by Gly (V325G), deletion of residues 93–97
(Del93–97), and deletion–substitution of residues 953–956
by Ser (EETA956S), which shows inward leak currents under physiological
conditions. The first three mutations affect the structural context
of the key ion-binding residue Glu327 at binding site II, which leads
to the loss of the ability to bind ions correctly and to occlude the
pump. The mutated residue in L97R is more hydrated, which ultimately
leads to the observed proton leak. V325G mimics the structural behavior
of L97R; however, it does not promote the hydration of surrounding
residues. In Del93–97, a broader opening is observed because
of the rearrangement of the kinked transmembrane helix 1, M1, which
may explain the sodium leak measured with the mutant. The last mutant,
EETA956S, opens an additional water pathway near the C-terminus, affecting
the III sodium-specific binding site. The results are in excellent
agreement with recent electrophysiology measurements and suggest how
three mutations prevent the occlusion of the Na<sup>+</sup>,K<sup>+</sup>-ATPase, with the possibility of transforming the pump into
a passive ion channel, whereas the fourth mutation provides insight
into the sodium binding in the E1 state