5 research outputs found
Binding of Capsaicin to the TRPV1 Ion Channel
Transient
receptor potential (TRP) ion channels constitute a notable
family of cation channels involved in the ability of an organisms
to detect noxious mechanical, thermal, and chemical stimuli that give
rise to the perception of pain, taste, and changes in temperature.
One of the most experimentally studied agonist of TRP channels is
capsaicin, which is responsible for the burning sensation produced
when chili pepper is in contact with organic tissues. Thus, understanding
how this molecule interacts and regulates TRP channels is essential
to high impact pharmacological applications, particularly those related
to pain treatment. The recent publication of a three-dimensional structure
of the vanilloid receptor 1 (TRPV1) in the absence and presence of
capsaicin from single particle electron cryomicroscopy experiments
provides the opportunity to explore these questions at the atomic
level. In the present work, molecular docking and unbiased and biased
molecular dynamics simulations were employed to generate a structural
model of the capsaicināchannel complex. In addition, the standard
free energy of binding was estimated using alchemical transformations
coupled with conformational, translational, and orientational restraints
on the ligand. Key binding modes consistent with previous experimental
data are identified, and subtle but essential dynamical features of
the binding site are characterized. These observations shed some light
into how TRPV1 interacts with capsaicin, and may help to refine design
parameters for new TRPV1 antagonists, and potentially guide further
developments of TRP channel modulators
Transferable Mixing of Atomistic and Coarse-Grained Water Models
Dual-resolution approaches for molecular
simulations combine the
best of two worlds, providing atomic details in regions of interest
and coarser but much faster descriptions of less-relevant parts of
molecular systems. Given the abundance of water in biomolecular systems,
reducing the computational cost of simulating bulk water without perturbing
the soluteās properties is a very attractive strategy. Here
we show that the coarse-grained model for water called WatFour (WT4)
can be combined with any of the three most used water models for atomistic
simulations (SPC, TIP3P, and SPC/E) without modifying the characteristics
of the atomistic solvent and solutes. The equivalence of fully atomistic
and hybrid solvation approaches is assessed by comparative simulations
of pure water, electrolyte solutions, and the Ī²1 domain of streptococcal
protein G, for which comparisons between experimental and calculated
chemical shifts at <sup>13</sup>CĪ± are equivalent
Mixing Atomistic and Coarse Grain Solvation Models for MD Simulations: Let WT4 Handle the Bulk
Accurate simulation of biomolecular systems requires
the consideration
of solvation effects. The arrangement and dynamics of water close
to a solute are strongly influenced by the solute itself. However,
as the soluteāsolvent distance increases, the water properties
tend to those of the bulk liquid. This suggests that bulk regions
can be treated at a coarse grained (CG) level, while keeping the atomistic
details around the solute. Since water represents about 80% of any
biological system, this approach may offer a significant reduction
in the computational cost of simulations without compromising atomistic
details. We show here that mixing the popular SPC water model with
a CG model for solvation (called WatFour) can effectively mimic the
hydration, structure, and dynamics of molecular systems composed of
pure water, simple electrolyte solutions, and solvated macromolecules.
As a nontrivial example, we present simulations of the SNARE membrane
fusion complex, a trimeric proteināprotein complex embedded
in a double phospholipid bilayer. Comparison with a fully atomistic
reference simulation illustrates the equivalence between both approaches
Lateral Fenestrations in K<sup>+</sup>āChannels Explored Using Molecular Dynamics Simulations
Potassium channels are of paramount
physiological and pathological
importance and therefore constitute significant drug targets. One
of the keys to rationalize the way drugs modulate ion channels is
to understand the ability of such small molecules to access their
respective binding sites, from which they can exert an activating
or inhibitory effect. Many computational studies have probed the energetics
of ion permeation, and the mechanisms of voltage gating, but little
is known about the role of fenestrations as possible mediators of
drug entry in potassium channels. To explore the existence, structure,
and conformational dynamics of transmembrane fenestrations accessible
by drugs in potassium channels, molecular dynamics simulation trajectories
were analyzed from three potassium channels: the open state voltage-gated
channel Kv1.2, the G protein-gated inward rectifying channel GIRK2
(Kir3.2), and the human two-pore domain TWIK-1 (K2P1.1). The main
results of this work were the identification of the sequence identity
of four main lateral fenestrations of similar length and with bottleneck
radius in the range of 0.9ā2.4 Ć
for this set of potassium
channels. It was found that the fenestrations in Kv1.2 and Kir3.2
remain closed to the passage of molecules larger than water. In contrast,
in the TWIK-1 channel, both open and closed fenestrations are sampled
throughout the simulation, with bottleneck radius shown to correlate
with the random entry of lipid membrane molecules into the aperture
of the fenestrations. Druggability scoring function analysis of the
fenestration regions suggests that Kv and Kir channels studied are
not druggable in practice due to steric constraining of the fenestration
bottleneck. A high (>50%) fenestration sequence identity was found
in each potassium channel subfamily studied, Kv1, Kir3, and K2P1.
Finally, the reported fenestration sequence of TWIK-1 compared favorably
with another channel, K2P channel TREK-2, reported to possess open
fenestrations, suggesting that K2P channels could be druggable via
fenestrations, for which we reported atomistic detail of the fenestration
region, including the flexible residues M260 and L264 that interact
with POPC membrane in a concerted fashion with the aperture and closure
of the fenestrations
Small Details Matter: The 2ā²-Hydroxyl as a Conformational Switch in RNA
While DNA is mostly a primary carrier
of genetic information and
displays a regular duplex structure, RNA can form very complicated
and conserved 3D structures displaying a large variety of functions,
such as being an intermediary carrier of the genetic information,
translating such information into the protein machinery of the cell,
or even acting as a chemical catalyst. At the base of such functional
diversity is the subtle balance between different backbone, nucleobase,
and ribose conformations, finely regulated by the combination of hydrogen
bonds and stacking interactions. Although an apparently simple chemical
modification, the presence of the 2ā²OH in RNA has a profound
effect in the ribonucleotide conformational balance, adding an extra
layer of complexity to the interactions network in RNA. In the present
work, we have combined database analysis with extensive molecular
dynamics, quantum mechanics, and hybrid QM/MM simulations to provide
direct evidence on the dramatic impact of the 2ā²OH conformation
on sugar puckering. Calculations provide evidence that proteins can
modulate the 2ā²OH conformation to drive sugar repuckering,
leading then to the formation of bioactive conformations. In summary,
the 2ā²OH group seems to be a primary molecular switch contributing
to specific proteināRNA recognition