Biomedical subjects

Mounir Tarek

Publications and source records attributed to Mounir Tarek.

10 recordsLinked to original sources

PubMed2006

K+ conduction in the selectivity filter of potassium channels is monitored by the charge distribution along their sequence.

Potassium channels display a high conservation of sequence of the selectivity filter (SF), yet nature has designed a variety of channels that present a wide range of absolute rates of K(+) permeation. In KcsA, the structural archetype for K channels, under physiological concentrations, two K(+) ions reside in the SF in configurations 1,3 (up state) and 2,4 (down state) and ion conduction is believed to follow a throughput cycle involving a transition between these states. Using free-energy calculations of KcsA, Kv1.2, and mutant channels, we show that this transition is characterized by a channel-dependent energy barrier. This barrier is strongly influenced by the charges partitioned along the sequence of each channel. These results unveil therefore how, for similar structures of the SF, the rate of K(+) turnover may be fine-tuned within the family of potassium channels.

Amino Acid Sequence↗

PubMed2006

Molecular restraints in the permeation pathway of ion channels.

Ion channels assist and control the diffusion of ions through biological membranes. The conduction process depends on the structural characteristics of these nanopores, among which are the hydrophobicity and the afforded diameter of the conduction pathway. In this contribution, we use full atomistic free-energy molecular dynamics simulations to estimate the effect of such characteristics on the energetics of ion conduction through the activation gate of voltage-gated potassium (Kv) channels. We consider specifically the ionic translocation through three different permeation pathways, corresponding to the activation gate of an atomistic model of Shaker channels in closed and partially opened conformations, and that of the open conformation of the Kv1.2 channel. In agreement with experiments, we find that the region of Val(478) constitutes the main gate. The conduction is unfavorable through this gate when the constriction is smaller than an estimated threshold of 4.5-5.0 A, mainly due to incomplete coordination-hydration of the ion. Above this critical size, e.g., for the Kv1.2, the valine gate is wide enough to allow fully coordination of the ion and therefore its diffusion on a flat energy surface. Similar to other ion channels, Kv channels appear therefore to regulate diffusion by constricting hydrophobic regions of the permeation pathway.

Amino Acid Motifs↗

PubMed2006

Environment of the gating charges in the Kv1.2 Shaker potassium channel.

Recently, the structure of the Shaker channel Kv1.2 has been determined at a 2.9-angstroms resolution. This opens new possibilities in deciphering the mechanism underlying the function of voltage-gated potassium (Kv) channels. Molecular dynamics simulations of the channel, embedded in a membrane environment show that the channel is in its open state and that the gating charges carried by S4 are exposed to the solvent. The hydrated environment of S4 favors a local collapse of the electrostatic potential, which generates high electric-field gradients around the arginine gating charges. Comparison to experiments suggests furthermore that activation of the channel requires mainly a lateral displacement of S4. Overall, the results agree with the transporter model devised for Kv channels from electrophysiology experiments, and provide a possible pathway for the mechanistic response to membrane depolarization.

Computer Simulation↗

PubMed2006

Interaction of a peptide nanotube with a water-membrane interface.

Inserting peptide nanotubes into lipid bilayers modulates the permeability properties of the cell wall, thus conferring potential bacteriocidal capability. Interaction of a peptide nanotube formed by eight cyclo[RRKWLWLW] subunits with the surface of a hydrated dimyristoylphosphatidylcholine bilayer is investigated using molecular dynamics simulations. The present sequence of alternated D-L-alpha-amino acids has been shown to yield remarkable antibacterial in vitro activity, and the chosen topoisomer corresponds to the optimum amphipathy of the tubular structure, whereby non-polar and charged side chains are segregated by the aqueous interface. The cohesion of the nanotube is ensured by a scaffold of intermolecular hydrogen bonds between adjacent cyclic peptides, supplemented by favorable like-charged contacts of arginine side chains. It is further reinforced by interactions of charged residues with the lipid head groups and of non-polar residues with the lipid acyl chains. The simulation reveals a partial breaking of the synthetic channel accompanying its early insertion into the lipid bilayer. The latter opens new questions about how peptide nanotubes permeate the membrane, in particular whether or not (i) self-assembly precedes partitioning and (ii) translocation occurs with the complete tubular structure.

Computer Simulation↗

PubMed2005

Probing a model of a GPCR/ligand complex in an explicit membrane environment: the human cholecystokinin-1 receptor.

A three-dimensional model structure of a complex formed by a G-protein-coupled receptor (GPCR) and an agonist ligand is probed and refined using molecular-dynamics simulations and free energy calculations in a realistic environment. The model of the human receptor of cholecystokinin associated to agonist ligand CCK9 was obtained from a synergistic procedure combining site-directed mutagenesis experiments and in silico modeling. The 31-ns molecular-dynamics simulation in an explicit membrane environment indicates that both the structure of the receptor and its interactions with the ligand are robust. Whereas the secondary structure of the alpha-helix bundle is well preserved, the region of the intracellular loops exhibits a significant flexibility likely to be ascribed to the absence of G-protein subunits in the model. New insight into the structural features of the binding pocket is gained, in particular, the interplay of the ligand with both the receptor and internal water molecules. Water-mediated interactions are shown to participate in the binding, hence, suggesting additional site-directed mutagenesis experiments. Accurate free energy calculations on mutated ligands provide differences in the receptor-ligand binding affinity, thus offering a direct, quantitative comparison to experiment. We propose that this detailed consistency-checking procedure be used as a routine refinement step of in vacuo GPCR models, before further investigation and application to structure-based drug design.

Cell Membrane↗

PubMed2005

Membrane electroporation: a molecular dynamics simulation.

We present results of molecular dynamics simulations of lipid bilayers under a high transverse electrical field aimed at investigating their electroporation. Several systems are studied, namely 1), a bare bilayer, 2), a bilayer containing a peptide nanotube channel, and 3), a system with a peripheral DNA double strand. In all systems, the applied transmembrane electric fields (0.5 V.nm(-1) and 1.0 V.nm(-1)) induce an electroporation of the lipid bilayer manifested by the formation of water wires and water channels across the membrane. The internal structures of the peptide nanotube assembly and that of the DNA strand are hardly modified under field. For system 2, no perturbation of the membrane is witnessed at the vicinity of the channel, which indicates that the interactions of the peptide with the nearby lipids stabilize the bilayer. For system 3, the DNA strand migrates to the interior of the membrane only after electroporation. Interestingly enough, switching of the external transmembrane potential in cases 1 and 2 for few nanoseconds is enough to allow for complete resealing and reconstitution of the bilayer. We provide evidence that the electric field induces a significant lateral stress on the bilayer, manifested by surface tensions of magnitudes in the order of 1 mN.m(-1). This study is believed to capture the essence of several dynamical phenomena observed experimentally and provides a framework for further developments and for new applications.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed2004

Methyl group dynamics as a probe of the protein dynamical transition.

Hydrated proteins undergo a dynamical transition around 200 K from glasslike to liquidlike motion. Molecular dynamics simulations have been used to study the temperature dependence of the dynamics of ribonuclease A in the hydrated crystal, a model dehydrated powder, and aqueous solution. Changes in the dynamics accompanying the transition throughout the protein have been quantified in terms of the mean-squared fluctuations (MSFs) of methyl hydrogen atoms on the 100 ps time scale. In solution at 300 K the MSFs span a broad distribution, consistent with NMR relaxation measurements. The MSF distribution in the hydrated crystal at 300 K is qualitatively similar to the solution result, except for a slight shift to lower values, and dehydration results in a dramatic shift of the MSFs to lower values. As the temperature is lowered, the whole distribution of methyl group fluctuations in the hydrated crystal shifts to lower values. Most of the methyl groups in the hydrated protein display a nonlinear temperature dependence with a dynamical transition at approximately 200 K, but most methyl groups do not undergo a transition in the dehydrated protein. We conclude that the dynamical transition occurs throughout most of the protein and that solvent is required for the transition.

Computer Simulation↗

PubMed2004

Coupled motions between pore and voltage-sensor domains: a model for Shaker B, a voltage-gated potassium channel.

A high-resolution crystal structure of KvAP, an archeabacterial voltage-gated potassium (Kv) channel, complexed with a monoclonal Fab fragment has been recently determined. Based on this structure, a mechanism for the activation (opening) of Kv channels has been put forward. This mechanism has since been criticized, suggesting that the resolved structure is not representative of the family of voltage-gated potassium channels. Here, we propose a model of the transmembrane domain of Shaker B, a well-characterized Kv channel, built by homology modeling and docking calculations. In this model, the positively charged S4 helices are oriented perpendicular to the membrane and localized in the groove between segments S5 and S6 of adjacent subunits. The structure and the dynamics of the full atomistic model embedded in a hydrated lipid bilayer were investigated by means of two large-scale molecular dynamics simulations under transmembrane-voltage conditions known to induce, respectively, the resting state (closed) and the activation (opening) of voltage-gated channels. Upon activation, the model undergoes conformational changes that lead to an increase of the hydration of the charged S4 helices, correlated with an upward translation and a tilting of the latter, concurrently with movements of the S5 helices and the activation gate. Although small, these conformational changes ultimately result in an alteration of the ion-conduction pathway. Our findings support the transporter model devised by Bezanilla and collaborators, and further underline the crucial role played by internal hydration in the activation of the channel.

Computer Simulation↗

PubMed2003

Molecular dynamics investigation of an oriented cyclic peptide nanotube in DMPC bilayers.

Nanotubes resulting from the self-assembly of cyclic peptides formed by eight alpha-amino acids and inserted into lipid bilayers have been shown to function as synthetic, integral transmembrane channels. A nanotube consisting of eight cyclo[(L-Trp-D-Leu)(3)-L-Gln-D-Leu] subunits, organized in an antiparallel, beta-sheetlike channel embedded in a hydrated dimyristoylphosphatidylcholine bilayer was investigated in an 8-ns molecular dynamics trajectory. This large-scale statistical simulation brings to light not only the atomic-level structural features of the synthetic channel, but also its dynamical properties. Overall, the nanotube conserves its hollow tubular structure. The calculation reproduces the tilt of the channel with respect to the normal of the bilayer, in reasonable agreement with experiment. The results show a dislocation of the nanotube indicative of a possible disassembly process that may influence the channel conduction. The dynamics of the water in the hollow tubular structure has been characterized, and the conductance of the channel has been estimated. Transport properties of the peptide nanotube are discussed in comparison with other transporters.

Computer Simulation↗

PubMed2002

Effects of the nonimmobilizer hexafluroethane on the model membrane dimyristoylphosphatidylcholine.

BACKGROUND: Nonimmobilizers are agents that lack anesthetic properties, although their chemical structure is very similar to known anesthetics. The primary action site of both agents, whether at the membrane or target protein level, is still a matter of debate. However, increasing evidence points to the distinct modifications of the membrane physical properties that such agents induce. Such modification may play a role in the mechanism of anesthesia, and may therefore be related to the differences in their clinical behavior. METHODS: Molecular dynamics (MD) computer simulations have been used to investigate the distribution of a nonimmobilizer, hexafluroethane (HFE, C(2)F(6)), in a lipid membrane. The biologically relevant liquid-crystal phase of a hydrated dimyristoyl phosphatidyl choline (DMPC) bilayer was used as a membrane model. Two MD simulations corresponding to HFE mole fractions of 6% and 25% have been performed at room temperature and constant ambient pressure, for a duration of 2 nanoseconds each. RESULTS: The equilibrium configurations of HFE in the bilayer show that the nonimmobilizer molecules are evenly distributed along the lipid hydrocarbon chains with a slight preference for the bilayer center. This partitioning induces an expansion of the bilayer thickness and a lateral contraction of the membrane (decrease of the area per lipid). The presence of HFE has essentially no effect on the lipid acyl chain conformations in agreement with nuclear magnetic resonance (NMR) measurements of the chain order parameters. The partitioning of the nonimmobilizer does not influence the orientation of the lipid head-group dipole moment. CONCLUSIONS: The modifications induced by the presence of the nonimmobilizer HFE on a model membrane are distinct from those previously found for halothane (CF(3)CHBrCl), its anesthetic analogue, and appear to result from different distributions in the lipid bilayer. The results of the MD simulations show that (1) the changes in the average area per lipid and in the membrane thickness are opposite for the two agents and (2) HFE induces no change in the lipid head-group orientation, in contrast to halothane. These different effects (1) on the physical properties of the lipid bilayer and (2) on the electrostatic properties of the membrane-water interface may be linked to different clinical effects, and thus might contribute to the mechanism of general anesthesia.

Algorithms↗