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D P Tieleman

Publications and source records attributed to D P Tieleman.

At least 19 recordsLinked to original sources
PubMed2006

Structural investigation of syringomycin-E using molecular dynamics simulation and NMR.

Syringomycin-E (SR-E) is a cyclic lipodepsinonapeptide produced by certain strains of the bacterium Pseudomonas syringae pv. syringae. It shows inhibitory effects against many fungal species, including human pathogens. Its primary biological target is the plasma membrane, where it forms channels comprised of at least six SR-E molecules. The high-resolution structure of SR-E and the structure of the channels are currently not known. In this paper, we investigate in atomic detail the molecular features of SR-E in water by NMR and in water and octane by molecular dynamics simulation (MD). We built a model of the peptide and examined its structure in water and octane in 200 ns MD simulations both with and without distance restraints derived from NMR NOE data. The resulting trajectories show good agreement with the measured NOEs and circular dichroism data from the literature and provide atomistic models of SR-E that are an important step toward a better understanding of the antifungal and antibacterial activity of this peptide.

Biophysical Phenomena↗
PubMed2005

Orientation and dynamics of benzyl alcohol and benzyl alkyl ethers dissolved in nematic lyotropic liquid crystals. 2H NMR and molecular dynamics simulations.

Most drugs have to cross cell membranes to reach their final target. A better understanding of the distribution, interactions, and dynamics of biologically active molecules in model bilayers is of fundamental importance in understanding drug functioning and design. 2H NMR quadrupole splittings (delta nu(Q)) and longitudinal relaxation times (T1) from the aromatic ring of benzyl alcohol-d5 (C0), a commonly used anesthetic, and a series of linear alkyl benzyl-d5 ethers with chain lengths from 1 to 12 carbon atoms (C1-C12), were measured. The molecules were dissolved in a nematic discotic lyotropic liquid crystal solution made of tetradecyltrimethylammonium chloride (TTAC)/decanol (DeOH)/NaCl/H2O. Values of delta nu(Q) and T1 from 1,1-dideuteriodecanol (15% enriched) and DHO (H2O with 0.2% D2O) were also measured. Delta nu(Q) of DeOH and DHO remained constant throughout the series. The value of delta nu(Q) of the para position of the ring (delta nu(p)) in C1 is 30% smaller than the delta nu(p) of C0. This is attributed to the existence of an H-bond between the alcohol hydroxyl proton and the solvent, which influences the average orientation of the ring. The relaxation data show that T1o,m is always longer than T1p and both decrease with the increase in alkyl chain length. Molecular dynamics simulations of the experimentally studied systems were performed. The aggregate was represented as a bilayer. The distribution, average orientation, and order parameters of the aromatic ring of the guest molecules in the bilayer were examined. Rotational correlation functions of all the C-D bonds and the OH bond from H2O were evaluated, allowing an estimate of the correlation times and T1. According to these results all spins relax in extreme narrowing conditions, except DeOH. Experimental and calculated T1 values differ at most by a factor of 3. However, the order of magnitude and the observed trends are well reproduced by the calculations. The aromatic ring of C0 possesses a unique average orientation in the bilayer. For the ether series, the orientation is modified and the C2 symmetry axis of the aromatic ring is exchanging between two orientations averaging the quadrupole splittings from the ortho and meta positions. The simulation supports the existence of an H-bond between C0 and the solvent not found in the ethers, which should be responsible for the observed differences.

Benzyl Alcohol↗
PubMed2004

Structure and aggregation number of a lyotropic liquid crystal: a fluorescence quenching and molecular dynamics study.

The structure and aggregation number of a discotic lyotropic liquid crystal, prepared from tetradecyltrimethylammonium chloride (TDTMACl)/decanol (DeOH)/NaCl/H2O, have been examined using fluorescence quenching of pyrene by hexadecylpyridinium chloride and molecular dynamics (MD). The fluorescence method gives an aggregation number of 258 +/- 25 units (DeOH + TDTMACl). From the MD simulation, a lower limit for the aggregate dimension of 130 units of DeOH + TDTMACl is predicted. A stable oblate aggregate of 240 units was studied in detail. A strong polarization between the ammonium headgroups and chloride ions is observed from the calculated trajectory. DeOH headgroups are located, on average, 0.3 nm more to the interior of the aggregate than the TDTMACl headgroup and contribute to widening the interface by forming H-bonds with water. The radial distribution function of the ammonium headgroup shows that there are 16 water molecules in the first solvation sphere. The diagonal elements of the order parameter tensor of the tail atoms of both surfactants indicate that the interior of the micelle preserves about the same degree of order as at the interface, up to the last three atoms of the aliphatic chain, where the order starts to decrease.

Journal Article↗
PubMed2003

Pores formed by the nicotinic receptor m2delta Peptide: a molecular dynamics simulation study.

The M2delta peptide self-assembles to form a pentameric bundle of transmembrane alpha-helices that is a model of the pore-lining region of the nicotinic acetylcholine receptor. Long (>15 ns) molecular dynamics simulations of a model of the M2delta(5) bundle in a POPC bilayer have been used to explore the conformational dynamics of the channel assembly. On the timescale of the simulation, the bundle remains relatively stable, with the polar pore-lining side chains remaining exposed to the lumen of the channel. Fluctuations at the helix termini, and in the helix curvature, result in closing/opening transitions at both mouths of the channel, on a timescale of approximately 10 ns. On average, water within the pore lumen diffuses approximately 4x more slowly than water outside the channel. Examination of pore water trajectories reveals both single-file and path-crossing regimes to occur at different times within the simulation.

Amino Acid Sequence↗
PubMed2001

Molecular dynamics simulation of a lipid diamond cubic phase.

This paper presents the first atomistic simulation of a cubic membrane phase. Using the molecular dynamics simulation technique both the global and the local organization of glycerolmonoolein molecules inside the diamond cubic phase are studied. Multinanosecond simulations reveal that the center of the cubic bilayer remains close to the infinite periodic minimal surface that describes the diamond geometry. We further show that the equilibrium structure of the surfactant molecules inside the cubic phase is very similar to their structure inside a simulated lamellar bilayer. The small differences arise from the packing constraints of the surfactants within the cubic phase which has an area per surfactant that increases toward the bilayer center.

Computer Simulation↗
PubMed2001

Proline-induced hinges in transmembrane helices: possible roles in ion channel gating.

A number of ion channels contain transmembrane (TM) alpha-helices that contain proline-induced molecular hinges. These TM helices include the channel-forming peptide alamethicin (Alm), the S6 helix from voltage-gated potassium (Kv) channels, and the D5 helix from voltage-gated chloride (CLC) channels. For both Alm and KvS6, experimental data implicate hinge-bending motions of the helix in an aspect of channel gating. We have compared the hinge-bending motions of these TM helices in bilayer-like environments by multi-nanosecond MD simulations in an attempt to describe motions of these helices that may underlie possible modes of channel gating. Alm is an alpha-helical channel-forming peptide, which contains a central kink associated with a Gly-x-x-Pro motif in its sequence. Simulations of Alm in a TM orientation for 10 ns in an octane slab indicate that the Gly-x-x-Pro motif acts as a molecular hinge. The S6 helix from Shaker Kv channels contains a Pro-Val-Pro motif. Modeling studies and recent experimental data suggest that the KvS6 helix may be kinked in the vicinity of this motif. Simulations (10 ns) of an isolated KvS6 helix in an octane slab and in a POPC bilayer reveal hinge-bending motions. A pattern-matching approach was used to search for possible hinge-bending motifs in the TM helices of other ion channel proteins. This uncovered a conserved Gly-x-Pro motif in TM helix D5 of CLC channels. MD simulations of a model of hCLC1-D5 spanning an octane slab suggest that this channel also contains a TM helix that undergoes hinge-bending motion. In conclusion, our simulations suggest a model in which hinge-bending motions of TM helices may play a functional role in the gating mechanisms of several different families of ion channels.

Alamethicin↗
PubMed2001

Voltage-dependent insertion of alamethicin at phospholipid/water and octane/water interfaces.

Understanding the binding and insertion of peptides in lipid bilayers is a prerequisite for understanding phenomena such as antimicrobial activity and membrane-protein folding. We describe molecular dynamics simulations of the antimicrobial peptide alamethicin in lipid/water and octane/water environments, taking into account an external electric field to mimic the membrane potential. At cis-positive potentials, alamethicin does not insert into a phospholipid bilayer in 10 ns of simulation, due to the slow dynamics of the peptide and lipids. However, in octane N-terminal insertion occurs at field strengths from 0.33 V/nm and higher, in simulations of up to 100 ns duration. Insertion of alamethicin occurs in two steps, corresponding to desolvation of the Gln7 side chain, and the backbone of Aib10 and Gly11. The proline induced helix kink angle does not change significantly during insertion. Polyalanine and alamethicin form stable helices both when inserted in octane and at the water/octane interface, where they partition in the same location. In water, both polyalanine and alamethicin partially unfold in multiple simulations. We present a detailed analysis of the insertion of alamethicin into the octane slab and the influence of the external field on the peptide structure. Our findings give new insight into the mechanism of channel formation by alamethicin and the structure and dynamics of membrane-associated helices.

Alamethicin↗
PubMed2001

Towards the design and computational characterization of a membrane protein.

The design of a transmembrane four-helix bundle is described. We start with an idealized four-helix bundle geometry, then use statistical information to build a plausible transmembrane bundle. Appropriate residues are chosen using database knowledge on the sequences of membrane helices and loops, then the packing of the bundle core is optimized, and favorable side chain rotamers from rotamer libraries are selected. Next, we use explicit physical knowledge from biomolecular simulation force fields and molecular dynamics simulations to test whether the designed structure is physically possible. These procedures test whether the designed protein will indeed be alpha-helical, well packed and stable over a time scale of several nanoseconds in a realistic lipid bilayer environment. We then test a modeling approach that does not include sophisticated database knowledge about proteins, but rather relies on applying our knowledge of the physics that governs protein motions. This independent validation of the design is based on simulated annealing and restrained molecular dynamics simulation in vacuo, comparable to procedures used to refine NMR and X-ray structures.

Computer Simulation↗
PubMed2000

Structure and dynamics of the pore-lining helix of the nicotinic receptor: MD simulations in water, lipid bilayers, and transbilayer bundles.

Multiple nanosecond duration molecular dynamics simulations on the pore-lining M2 helix of the nicotinic acetylcholine receptor reveal how its structure and dynamics change as a function of environment. In water, the M2 helix partially unfolds to form a molecular hinge in the vicinity of a central Leu residue that has been implicated in the mechanism of ion channel gating. In a phospholipid bilayer, either as a single transmembrane helix, or as part of a pentameric helix bundle, the M2 helix shows less flexibility, but still exhibits a kink in the vicinity of the central Leu. The single M2 helix tilts relative to the bilayer normal by 12 degrees, in agreement with recent solid state NMR data (Opella et al., Nat Struct Biol 6:374-379, 1999). The pentameric helix bundle, a model for the pore domain of the nicotinic receptor and for channels formed by M2 peptides in a bilayer, is remarkably stable over a 2-ns MD simulation in a bilayer, provided one adjusts the pK(A)s of ionizable residues to their calculated values (when taking their environment into account) before starting the simulation. The resultant transbilayer pore shows fluctuations at either mouth which transiently close the channel. Proteins 2000;39:47-55.

Computer Simulation↗
PubMed2000

Exploring models of the influenza A M2 channel: MD simulations in a phospholipid bilayer.

The M2 protein of influenza A virus forms homotetrameric helix bundles, which function as proton-selective channels. The native form of the protein is 97 residues long, although peptides representing the transmembrane section display ion channel activity, which (like the native channel) is blocked by the antiviral drug amantadine. As a small ion channel, M2 may provide useful insights into more complex channel systems. Models of tetrameric bundles of helices containing either 18 or 22 residues have been simulated while embedded in a fully hydrated 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphatidylcholine bilayer. Several different starting models have been used. These suggest that the simulation results, at least on a nanosecond time scale, are sensitive to the exact starting structure. Electrostatics calculations carried out on a ring of four ionizable aspartate residues at the N-terminal mouth of the channel suggest that at any one time, only one will be in a charged state. Helix bundle models were mostly stable over the duration of the simulation, and their helices remained tilted relative to the bilayer normal. The M2 helix bundles form closed channels that undergo breathing motions, alternating between a tetramer and a dimer-of-dimers structure. Under these conditions either the channel forms a pocket of trapped waters or it contains a column of waters broken predominantly at the C-terminal mouth of the pore. These waters exhibit restricted motion in the pore and are effectively "frozen" in a way similar to those seen in previous simulations of a proton channel formed by a four-helix bundle of a synthetic leucine-serine peptide (, Biophys. J. 77:2400-2410).

Amino Acid Sequence↗
PubMed1999

Simulation studies of the interaction of antimicrobial peptides and lipid bilayers.

Experimental studies of a number of antimicrobial peptides are sufficiently detailed to allow computer simulations to make a significant contribution to understanding their mechanisms of action at an atomic level. In this review we focus on simulation studies of alamethicin, melittin, dermaseptin and related antimicrobial, membrane-active peptides. All of these peptides form amphipathic alpha-helices. Simulations allow us to explore the interactions of such peptides with lipid bilayers, and to understand the effects of such interactions on the conformational dynamics of the peptides. Mean field methods employ an empirical energy function, such as a simple hydrophobicity potential, to provide an approximation to the membrane. Mean field approaches allow us to predict the optimal orientation of a peptide helix relative to a bilayer. Molecular dynamics simulations that include an atomistic model of the bilayer and surrounding solvent provide a more detailed insight into peptide-bilayer interactions. In the case of alamethicin, all-atom simulations have allowed us to explore several steps along the route from binding to the membrane surface to formation of transbilayer ion channels. For those antimicrobial peptides such as dermaseptin which prefer to remain at the surface of a bilayer, molecular dynamics simulations allow us to explore the favourable interactions between the peptide helix sidechains and the phospholipid headgroups.

Alamethicin↗
PubMed1999

The mechanism of channel formation by alamethicin as viewed by molecular dynamics simulations.

Alamethicin is a 20-residue channel-forming peptide that forms a stable amphipathic alpha-helix in membrane and membrane-mimetic environments. This helix contains a kink induced by a central Gly-X-X-Pro sequence motif. Alamethicin channels are activated by a cis positive transbilayer voltage. Channel activation is suggested to correspond to voltage-induced insertion of alamethicin helices in the bilayer. Alamethicin forms multi-conductance channels in lipid bilayers. These channels are formed by parallel bundles of transmembrane helices surrounding a central pore. A change in the number of helices per bundle switches the single channel conductance level. Molecular dynamics simulations of alamethicin in a number of different environments have been used to explore its channel-forming properties. These simulations include: (i) alamethicin in solution in water and in methanol; (ii) a single alamethicin helix at the surface of a phosphatidylcholine bilayer; (iii) single alamethicin helices spanning a phosphatidylcholine bilayer; and (iv) channels formed by bundles of 5, 6, 7 or 8 alamethicin helices spanning a phosphatidylcholine bilayer. The total simulation time is c. 30 ns. Thus, these simulations provide a set of dynamic snapshots of a possible mechanism of channel formation by this peptide.

Alamethicin↗
PubMed1999

Alamethicin helices in a bilayer and in solution: molecular dynamics simulations.

Alamethicin is an alpha-helical channel-forming peptide, which inserts into lipid bilayers in a voltage-dependent, asymmetrical fashion. Nanosecond molecular dynamics simulations have been used to compare alamethicin conformation and dynamics in three different environments: 1) in water; 2) in methanol; and 3) inserted into a lipid (palmitoyl-oleoyl-phosphatidylcholine) bilayer to form a transmembrane helix. In the bilayer and in methanol, there was little change (Calpha RMSD approximately 0.2 nm over 2 ns and 1 ns) from the initial helical conformation of the peptide. In water there were substantial changes (Calpha RMSD approximately 0.4 nm over 1 ns), especially in the C-terminal segment of the peptide, which lost its alpha-helical conformation. In the bilayer and in methanol, the alamethicin molecule underwent hinge-bending motion about its central Gly-X-X-Pro sequence motif. Analysis of H-bonding interactions revealed that the polar C-terminal side chains of alamethicin provided an "anchor" to the bilayer/water interface via formation of multiple H-bonds that persisted throughout the simulation. This explains why the preferred mode of helix insertion into the bilayer is N-terminal, which is believed to underlie the asymmetry of voltage activation of alamethicin channels.

Alamethicin↗
PubMed1999

An alamethicin channel in a lipid bilayer: molecular dynamics simulations.

We present the results of 2-ns molecular dynamics (MD) simulations of a hexameric bundle of Alm helices in a 1-palmitoyl-2-oleoylphosphatidylcholine bilayer. These simulations explore the dynamic properties of a model of a helix bundle channel in a complete phospholipid bilayer in an aqueous environment. We explore the stability and conformational dynamics of the bundle in a phospholipid bilayer. We also investigate the effect on bundle stability of the ionization state of the ring of Glu18 side chains. If all of the Glu18 side chains are ionised, the bundle is unstable; if none of the Glu18 side chains are ionized, the bundle is stable. pKA calculations suggest that either zero or one ionized Glu18 is present at neutral pH, correlating with the stable form of the helix bundle. The structural and dynamic properties of water in this model channel were examined. As in earlier in vacuo simulations (Breed et al., 1996 .Biophys. J. 70:1643-1661), the dipole moments of water molecules within the pore were aligned antiparallel to the helix dipoles. This contributes to the stability of the helix bundle.

Alamethicin↗
PubMed1999

Defining the transmembrane helix of M2 protein from influenza A by molecular dynamics simulations in a lipid bilayer.

Integral membrane proteins containing at least one transmembrane (TM) alpha-helix are believed to account for between 20% and 30% of most genomes. There are several algorithms that accurately predict the number and position of TM helices within a membrane protein sequence. However, these methods tend to disagree over the beginning and end residues of TM helices, posing problems for subsequent modeling and simulation studies. Molecular dynamics (MD) simulations in an explicit lipid and water environment are used to help define the TM helix of the M2 protein from influenza A virus. Based on a comparison of the results of five different secondary structure prediction algorithms, three different helix lengths (an 18mer, a 26mer, and a 34mer) were simulated. Each simulation system contained 127 POPC molecules plus approximately 3500-4700 waters, giving a total of approximately 18,000-21,000 atoms. Two simulations, each of 2 ns duration, were run for the 18mer and 26mer, and five separate simulations were run for the 34mer, using different starting models generated by restrained in vacuo MD simulations. The total simulation time amounted to 11 ns. Analysis of the time-dependent secondary structure of the TM segments was used to define the regions that adopted a stable alpha-helical conformation throughout the simulation. This analysis indicates a core TM region of approximately 20 residues (from residue 22 to residue 43) that remained in an alpha-helical conformation. Analysis of atomic density profiles suggested that the 18mer helix revealed a local perturbation of the lipid bilayer. Polar side chains on either side of this region form relatively long-lived H-bonds to lipid headgroups and water molecules.

Amino Acid Sequence↗
PubMed1999

Surface binding of alamethicin stabilizes its helical structure: molecular dynamics simulations.

Alamethicin is an amphipathic alpha-helical peptide that forms ion channels. An early event in channel formation is believed to be the binding of alamethicin to the surface of a lipid bilayer. Molecular dynamics simulations are used to compare the structural and dynamic properties of alamethicin in water and alamethicin bound to the surface of a phosphatidylcholine bilayer. The bilayer surface simulation corresponded to a loosely bound alamethicin molecule that interacted with lipid headgroups but did not penetrate the hydrophobic core of the bilayer. Both simulations started with the peptide molecule in an alpha-helical conformation and lasted 2 ns. In water, the helix started to unfold after approximately 300 ps and by the end of the simulation only the N-terminal region of the peptide remained alpha-helical and the molecule had collapsed into a more compact form. At the surface of the bilayer, loss of helicity was restricted to the C-terminal third of the molecule and the rod-shaped structure of the peptide was retained. In the surface simulation about 10% of the peptide/water H-bonds were replaced by peptide/lipid H-bonds. These simulations suggest that some degree of stabilization of an amphipathic alpha-helix occurs at a bilayer surface even without interactions between hydrophobic side chains and the acyl chain core of the bilayer.

Alamethicin↗
PubMed1998

Lipid properties and the orientation of aromatic residues in OmpF, influenza M2, and alamethicin systems: molecular dynamics simulations.

Molecular dynamics simulations allow a direct study of the structure and dynamics of membrane proteins and lipids. We describe the behavior of aromatic residues and lipid properties in POPE and POPC bilayer models with the Escherichia coli OmpF trimer, single alamethicin and Influenza M2 helices, 4-helix M2 bundles, and two alamethicin 6-helix channel models. The total simulation time is over 24 ns, of systems containing solvent, protein, and between 104 and 318 lipids. Various types of adjustment between lipids and proteins occur, depending on the size of the protein and the degree of hydrophobic mismatch between lipid and protein. Single helices cause little measurable effect on nearby lipids whereas the 4-helix bundles, 6-helix channel models, and OmpF cause a significant lowering of order parameters in nearby lipid chains, an increased difference between odd and even chain dihedrals in the magnitude of the trans dihedral fractions and dihedral transition rates, and in most cases a decreased gauche population and a decrease in bilayer thickness. An increased tilt of the lipid chains near the proteins can account for most of the observed decrease in order parameters. The orientation of tryptophans and tyrosines on the outside of the proteins is determined by packing at the protein exterior and non-specific hydrogen bonding with lipids and solvent. The tyrosines in the broad bands that delimit the hydrophobic exterior of OmpF show little change in orientation over one nanosecond. Their rings are oriented predominantly perpendicular to the bilayer plane, with the hydroxyl group pointing toward the lipid-water interface. Phenylalanines in OmpF, alamethicin, and Influenza M2 are more mobile and assume a variety of orientations.

Alamethicin↗