541 research outputs found
Computer simulation of partitioning of ten pentapeptides Ace-WLXLL at the cyclohexane/water and phospholipid/water interfaces
BACKGROUND: Peptide-membrane interactions play a key role in the binding, partitioning and folding of membrane proteins, the activity of antimicrobial and fusion peptides, and a number of other processes. To gain a better understanding of the thermodynamics of such interactions, White and Wimley created an interfacial hydrophobicity scale based of the transfer free energy from water to octanol or lipid bilayers of a series of synthetic peptapeptides (Ace-WLXLL, with X being any of the twenty natural amino acids) (White and Wimley (1996) Nat. Struct. Biol. 3, 842–848). In this study, we performed molecular dynamics simulations of a representative set of ten of these peptides (X = D, K, R, N, A, T, S, I, F and W) in two membrane mimetic interfaces: water-cyclohexane (10 ns) and a fully solvated dioleoylphosphatidylcholine (DOPC) bilayer (50 ns) using both constant pressure and constant area ensembles. We focus on partitioning of the ten peptides at the cyclohexane/water and lipid/water interfaces. RESULTS: The peptides rapidly equilibrate (< 2 ns) and partition at the cyclohexane/water interface. The X3 guest residue assumes average orientations that depend on the nature of the side chain. At the DOPC/water interface, dynamics is much slower and convergence is difficult to achieve on a 50 ns timescale. Nonetheless, all peptides partition to the lipid/water interface with distributions with widths of 1–2 nm. The peptides assume a broad range of side chain and backbone orientations and have only a small effect on the area of the unit cell. On average, hydrophobic guest residues partition deeper into the hydrophobic core than hydrophilic residues. In some cases the peptides penetrate sufficiently deep to somewhat affect the distribution of the C=C double bond in DOPC. The relative distribution of the X3 guest residue compared to W1 and L5 is similar in the water/cyclohexane and water/lipid simulations. Snapshots show mostly extended backbone conformations in both environments. There is little difference between simulations at a constant area of 0.66 nm(2 )and simulations at constant pressure that approximately yield the same average area of 0.66 nm(2). CONCLUSION: These peptides were designed to assume extended conformations, which is confirmed by the simulations. The distribution of the X3 side chain depends on its nature, and can be determined from molecular dynamics simulations. The time scale of peptide motion at a phospholipids-water interface is too long to directly calculate the experimentally measured hydrophobicity scale to test and improve the simulation parameters. This should be possible at the water/cyclohexane interface and likely will become feasible in the future for the phospholipids/water case
Water permeation through gramicidin A: Desformylation and the double helix: A molecular dynamics study
Multinanosecond molecular dynamics simulations of gramicidin A embedded in a dimyristoylphosphatidylcholine bilayer show a remarkable structural stability for both experimentally determined conformations: the head-to-head helical dimer and the double helix. Water permeability was found to be much higher in the double helical conformation, which is explained by lower hydrogen bond-mediated enthalpic barriers at the channel entrance and its larger pore size. Free-energy perturbation calculations show that the double helical structure is stabilized by the positive charges at the N termini introduced by the desformylation, whereas the helical dimer is destabilized. Together with the recent experimental observation that desformyl gramicidin conducts water hundredfold better than gramicidin, this suggests that desformyl gramicidin A predominantly occurs in the double helical conformation
Kinetic models of ion transport through a nanopore
Kinetic equations for the stationary state distribution function of ions
moving through narrow pores are solved for a number of one-dimensional models
of single ion transport. Ions move through pores of length , under the
action of a constant external field and of a concentration gradient. The
interaction of single ions with the confining pore surface and with water
molecules inside the pore are modelled by a Fokker-Planck term in the kinetic
equation, or by uncorrelated collisions with thermalizing centres distributed
along the pore. The temporary binding of ions to polar residues lining the pore
is modelled by stopping traps or energy barriers. Analytic expressions for the
stationary ion current through the pore are derived for several versions of the
model, as functions of key physical parameters. In all cases, saturation of the
current at high fields is predicted. Such simple models, for which results are
analytic, may prove useful in the study of the current/voltage relations of ion
channels through membranes
Conformational choreography of a molecular switch region in myelin basic protein—Molecular dynamics shows induced folding and secondary structure type conversion upon threonyl phosphorylation in both aqueous and membrane-associated environments
AbstractThe 18.5kDa isoform of myelin basic protein is essential to maintaining the close apposition of myelin membranes in central nervous system myelin, but its intrinsic disorder (conformational dependence on environment), a variety of post-translational modifications, and a diversity of protein ligands (e.g., actin and tubulin) all indicate it to be multifunctional. We have performed molecular dynamics simulations of a conserved central segment of 18.5kDa myelin basic protein (residues Glu80–Gly103, murine sequence numbering) in aqueous and membrane-associated environments to ascertain the stability of constituent secondary structure elements (α-helix from Glu80–Val91 and extended poly-proline type II from Thr92–Gly103) and the effects of phosphorylation of residues Thr92 and Thr95, individually and together. In aqueous solution, all four forms of the peptide bent in the middle to form a hydrophobic cluster. The phosphorylated variants were stabilized further by electrostatic interactions and formation of β-structures, in agreement with previous spectroscopic data. In simulations performed with the peptide in association with a dimyristoylphosphatidylcholine bilayer, the amphipathic α-helical segment remained stable and membrane-associated, although the degree of penetration was less in the phosphorylated variants, and the tilt of the α-helix with respect to the plane of the membrane also changed significantly with the modifications. The extended segment adjacent to this α-helix represents a putative SH3-ligand and remained exposed to the cytoplasm (and thus accessible to binding partners). The results of these simulations demonstrate how this segment of the protein can act as a molecular switch: an amphipathic α-helical segment of the protein is membrane-associated and presents a subsequent proline-rich segment to the cytoplasm for interaction with other proteins. Phosphorylation of threonyl residues alters the degree of membrane penetration of the α-helix and the accessibility of the proline-rich ligand and can stabilize a β-bend. A bend in this region of 18.5kDa myelin basic protein suggests that the N- and C-termini of the proteins can interact with different leaflets of the myelin membrane and explain how a single protein can bring them close together
Electrostatics of ions inside the nanopores and trans-membrane channels
A model of a finite cylindrical ion channel through a phospholipid membrane
of width separating two electrolyte reservoirs is studied. Analytical
solution of the Poisson equation is obtained for an arbitrary distribution of
ions inside the trans-membrane pore. The solution is asymptotically exact in
the limit of large ionic strength of electrolyte on the two sides of membrane.
However, even for physiological concentrations of electrolyte, the
electrostatic barrier sizes found using the theory are in excellent agreement
with the numerical solution of the Poisson equation. The analytical solution is
used to calculate the electrostatic potential energy profiles for pores
containing charged protein residues. Availability of a semi-exact interionic
potential should greatly facilitate the study of ionic transport through
nanopores and ion channels
Pokrovsky-Talapov Model at finite temperature: a renormalization-group analysis
We calculate the finite-temperature shift of the critical wavevector
of the Pokrovsky-Talapov model using a renormalization-group analysis.
Separating the Hamiltonian into a part that is renormalized and one that is
not, we obtain the flow equations for the stiffness and an arbitrary potential.
We then specialize to the case of a cosine potential, and compare our results
to well-known results for the sine-Gordon model, to which our model reduces in
the limit of vanishing driving wavevector Q=0. Our results may be applied to
describe the commensurate-incommensurate phase transition in several physical
systems and allow for a more realistic comparison with experiments, which are
always carried out at a finite temperature
Intermittent permeation of cylindrical nanopores by water
Molecular Dynamics simulations of water molecules in nanometre sized
cylindrical channels connecting two reservoirs show that the permeation of
water is very sensitive to the channel radius and to electric polarization of
the embedding material. At threshold, the permeation is {\emph{intermittent}}
on a nanosecond timescale, and strongly enhanced by the presence of an ion
inside the channel, providing a possible mechanism for gating. Confined water
remains surprisingly fluid and bulk-like. Its behaviour differs strikingly from
that of a reference Lennard-Jones fluid, which tends to contract into a highly
layered structure inside the channel.Comment: 4 pages, 4 figure
Simulations of a single membrane between two walls using a Monte Carlo method
Quantitative theory of interbilayer interactions is essential to interpret
x-ray scattering data and to elucidate these interactions for biologically
relevant systems. For this purpose Monte Carlo simulations have been performed
to obtain pressure P and positional fluctuations sigma. A new method, called
Fourier Monte-Carlo (FMC), that is based on a Fourier representation of the
displacement field, is developed and its superiority over the standard method
is demonstrated. The FMC method is applied to simulating a single membrane
between two hard walls, which models a stack of lipid bilayer membranes with
non-harmonic interactions. Finite size scaling is demonstrated and used to
obtain accurate values for P and sigma in the limit of a large continuous
membrane. The results are compared with perturbation theory approximations, and
numerical differences are found in the non-harmonic case. Therefore, the FMC
method, rather than the approximations, should be used for establishing the
connection between model potentials and observable quantities, as well as for
pure modeling purposes.Comment: 10 pages, 10 figure
Structural and functional basis for lipid synergy on the activity of the antibacterial peptide ABC transporter McjD
The lipid bilayer is a dynamic environment that consists of a mixture of lipids with different properties that regulate the function of membrane proteins; these lipids are either annular, masking the protein hydrophobic surface, or specific lipids, essential for protein function. In this study, using tandem mass spectrometry, we have identified specific lipids associated with the Escherichia coli ABC transporter McjD, which translocates the antibacterial peptide MccJ25. Using non-denaturing mass spectrometry, we show that McjD in complex with MccJ25 survives the gas-phase. Partial delipidation of McjD resulted in reduced ATPase activity and thermostability as shown by Circular Dichroism, both of which could be restored upon addition of defined E. coli lipids. We have resolved a phosphatidylglycerol lipid associated with McjD at 3.4 Ă… resolution, while molecular dynamic simulations carried out in different lipid environments assessed the binding of specific lipids to McjD. Combined, our data show a synergistic effect of zwitterionic and negatively charged lipids on the activity of McjD; the zwitterionic lipids provide structural stability to McjD whereas the negatively charged lipids are essential for its function
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