5 research outputs found
Mechanism of antagonist ligand binding to REV-ERBα
No full textAbstract REV-ERBα, a therapeutically promising nuclear hormone receptor, plays a crucial role in regulating various physiological processes such as the circadian clock, inflammation, and metabolism. However, the availability of chemical probes to investigate the pharmacology of this receptor is limited, with SR8278 being the only identified synthetic antagonist. Moreover, no X-ray crystal structures are currently available that demonstrate the binding of REV-ERBα to antagonist ligands. This lack of structural information impedes the development of targeted therapeutics. To address this issue, we employed Gaussian accelerated molecular dynamics (GaMD) simulations to investigate the binding pathway of SR8278 to REV-ERBα. For comparison, we also used GaMD to observe the ligand binding process of STL1267, for which an X-ray structure is available. GaMD simulations successfully captured the binding of both ligands to the receptor’s orthosteric site and predicted the ligand binding pathway and important amino acid residues involved in the antagonist SR8278 binding. This study highlights the effectiveness of GaMD in investigating protein–ligand interactions, particularly in the context of drug recognition for nuclear hormone receptors
Effects of Ionic Liquids on Aqueous Urea Solutions: Insights into the Ionic Liquid-Assisted Protein Renaturation
No full textWater Clathrates in Nanostructural Organization of Hydrated Ionic Liquids Manifest a Peculiar Density Trend
No full textIonic
liquid–water binary solutions have significantly expanded
the applications of ionic liquids (ILs) in chemical and biological
research. Therefore, considerable research has focused on measuring
the thermophysical properties of these binary mixtures. From low-to-moderate
concentrations of water, several IL/water mixtures exhibit deviations
from expected trends in thermophysical behavior. One such example
is a unique density trend observed for certain IL classes, which exhibit
a characteristic increase in density with the addition of small amounts
of water. Since water primarily interacts with the IL anion, such
deviations have always been explained in the context of anion–water
associations. Surprisingly, however, IL/water mixtures containing
different cations but a common lactate anion exhibit similar peculiarities
in density trends. Using atomistic level molecular dynamics simulations,
we show that diverse density trends are caused by cation-mediated
modulations in the IL nanostructure. Depending on its nature, the
IL cation can play a dual role in modulating the IL nanostructure:
(i) resist water-mediated breakdown of the nanostructure by interacting
with the anion very strongly, (ii) further strengthen the nanostructure
by incorporating water in the IL framework. The [emim] cation fails
to play both roles resulting in the density decrease, while the [tmg]
cation fulfills both roles leading to a density rise. The choline
cation resists the density fall by inducing the formation of “water-clathrates”
in the solution. Such occurrence of clathrates in IL/water binary
mixtures, reported for the first time in this study, further emphasizes
that the properties of ILs and its mixtures are not merely determined
by the chemical nature of the component ions, but also by their unique
nanostructural organizations. These unique nanostructural organizations
also manifest in their unusual dynamics
