3 research outputs found
Nontrivial Behavior of Water in the Vicinity and Inside Lipid Bilayers As Probed by Molecular Dynamics Simulations
The atomic-scale diffusion of water in the presence of several lipid bilayers mimicking biomembranes is characterized <i>via</i> unconstrained molecular dynamics (MD) simulations. Although the overall water dynamics corresponds well to literature data, namely, the efficient braking near polar head groups of lipids, a number of interesting and biologically relevant details observed in this work have not been sufficiently discussed so far; for instance, the fact that waters âsenseâ the membrane unexpectedly early, before water density begins to decrease. In this âtransitional zoneâ the velocity distributions of water and their H-bonding patterns deviate from those in the bulk solution. The boundaries of this zone are well preserved even despite the local (<1 nm size) perturbation of the lipid bilayer, thus indicating a decoupling of the surface and bulk dynamics of water. This is in excellent agreement with recent experimental data. Near the membrane surface, water movement becomes anisotropic, that is, solvent molecules preferentially move outward the bilayer. Deep in the membrane interior, the velocities can even exceed those in the bulk solvent and undergo large-scale fluctuations. The analysis of MD trajectories of individual waters in the middle part of the acyl chain region of lipids reveals a number of interesting rare phenomena, such as the fast (<i>ca.</i> 50 ps) breakthrough across the membrane or long-time (up to 750 ps) âroamingâ between lipid leaflets. The analysis of these events was accomplished to delineate the mechanisms of spontaneous water permeation inside the hydrophobic membrane core. It was shown that such nontrivial dynamics of water in an âalienâ environment is driven by the dynamic heterogeneities of the local bilayer structure and the formation of transient atomic-scale âdefectsâ in it. The picture observed in lipid bilayers is drastically different from that in a primitive membrane mimic, a hydrated cyclohexane slab. The possible biological impact of such phenomena in equilibrated lipid bilayers is discussed
Cardiotoxins: Functional Role of Local Conformational Changes
Cardiotoxins
(CTs) from snake venoms are a family of homologous
highly basic proteins that have extended hydrophobic patterns on their
molecular surfaces. CTs are folded into three β-structured loops
stabilized by four disulfide bridges. Being well-structured in aqueous
solution, most of these proteins are membrane-active, although the
exact molecular mechanisms of CT-induced cell damage are still poorly
understood. To elucidate the structureâfunction relationships
in CTs, a detailed knowledge of their spatial organization and local
conformational dynamics is required. Protein domain motions can be
either derived from a set of experimental structures or generated
via molecular dynamics (MD). At the same time, traditional clustering
algorithms in the Cartesian coordinate space often fail to properly
take into account the local large-scale dihedral angle transitions
that occur in MD simulations. This is because such perturbations are
usually offset by changes in the neighboring dihedrals, thus preserving
the overall protein fold. States with a âlocally perturbedâ
backbone were found in experimental 3D models of some globular proteins
and have been shown to be functionally meaningful. In this work, the
possibility of large-scale dihedral angle transitions in the course
of long-term MD in explicit water was explored for three CTs with
different membrane activities: CT 1, 2 (Naja oxiana) and CT A3 (Naja atra). Analysis
of the MD-derived distributions of backbone torsion angles revealed
several important common and specific features in the structural/dynamic
behavior of these proteins. First, large-amplitude transitions were
detected in some residues located in the functionally important loop
I region. The K5/L6 pair of residues was found to induce a perturbation
of the hydrophobic patterns on the molecular surface of CTsî¸reversible
breaking of a large nonpolar zone (âbottomâ) into two
smaller ones and their subsequent association. Second, the characteristic
sizes of these patterns perfectly coincided with the dimensions of
the nonpolar zones on the surfaces of model two-component (zwitterionic/anionic)
membranes. Taken together with experimental data on the CT-induced
leakage of fluorescent dye from such membranes, these results allowed
us to formulate a two-stage mechanism of CTâmembrane binding.
The principal finding of this study is that even local conformational
dynamics of CTs can seriously affect their functional activity via
a tuning of the membrane binding site â specific âhot
spotsâ (like the K5/L6 pair) in the protein structure
Kalium database
<p>Complete
copy of Kalium 2.0 database in the CSV format, six .csv files:<br></p>
<p>Activity.csv</p>
<p>Organism.csv</p>
<p>OrganismClass.csv</p>
<p>TargetCannel.csv</p>
<p>Toxin.csv</p>
<p>ToxinFamily.csv</p>
<p> </p>
<p>export_all_tc.csv
contains data in the format of concatenated Ligand cards presented in an
expanded manner. This looks similar to the export file, which can be downloaded
from Kalium by users, but contains additional information for each entry.</p>
<p> </p>
<p>In export_all_act.csv
each string describes the activity of every Kalium entry against a particular
target (potassium channel isoform).</p