[A molecular dynamics study of the interaction between domain I-BAR of the IRSp53 protein and negatively charged membranes].

The methods of computer simulation in full-atomic and large-grain approximations have been used to study specific interactions of the isolated domain I-BAR of the actin-binding protein IRSp53 and model membranes containing neutral phospholipids, as well as membranes containing high amounts of negatively charged PI(4,5)P2 phospholipids. It has been shown that the I-BAR domain does not interact with neutral lipids but induces the bending of the synthetic membrane rich in negatively charged phospholipids. A clusterization of charged lipids on the surface of the membrane at the sites of its interaction with the protein has been observed. This indicates that the interaction of the I-BAR protein with negatively charged lipids is of electrostatic and hydrophobic nature.

[The structural and dynamic model of the serotonin 5-HT3 receptor. Comparative analysis of the structure of the channel domain of pentameric ligand-gated ion channels].

The three-dimensional structure of the 5-HT3 receptor is currently unknown. An available structure of the nicotinic acetylcholine receptor closely related by homology to the 5-HT3 receptor was used as a template for the computer-based homology modeling of the 5-HT3 receptor. The study of the ion migration through the channel by the stirred molecular dynamics method has shown that the steric factor in the region of residue THR 279 and the region of GLU 272, ASP 293 influences the ion transmission. The characteristic of the close interaction between the ion and the amino acid substitutions of the 5-HT3 channel was studied by computing the energy profile using constraint force molecular dynamic simulations. The amino acid sequence responsible for selective ion transmission has been investigated. The structure of the channel domain of the serotonin 5-HT3 receptor as a universal functional unit of the ligand-gated ion channels was discussed.

[Comparative studies of structural properties of melittin in water and trifluroethanol/water mixture by the molecular dynamics method].

The structural properties and dynamic behavior of the antimicrobial peptide melittin in hydrophobic and polar environments have been investigated. The main characteristics of the secondary structure of melittin in different media have been analyzed, and compared with the data on the ideal alpha-helix. It has been shown that melittin is an alpha-helix bent in the region of residue Pro14; in this case, the N-terminus of the peptide tends to unfold, while the C-terminal segment (residues 14-23) retains the helical structure for 20 ns of the simulation. 2,2,2-Trifluoroethanol molecules stabilize the helical structure of the peptide through lowering the dielectric constant of the environment and preferential accumulation nearby particular segments of the polypeptide chain.

[Molecular dynamics of zervamicin II and its analogues in water and methanol].

A comparative study of the molecular dynamics of zervamicin II (an antimicrobial peptide from the peptaibol group, which has the channel-forming activity) in water and methanol has been performed. The influence of amino acid substitutions on the dynamics and stability of the peptide structure has been investigated. The amino acid sequence responsible for the absence of swivel motions in short peptaibols has been determined.

Steered molecular dynamics simulations of cobra cytotoxin interaction with zwitterionic lipid bilayer: no penetration of loop tips into membranes.

Cobra cytotoxins, small proteins of three-fingered toxin family, unspecifically damage membranes in different cells and artificial vesicles. However, the molecular mechanism of this damage is not yet completely understood. We used steered molecular dynamics simulations to study the interaction of cardiotoxin A3 from Naja atra cobra venom with hydrated 1-palmitoyl-2-oleoyl-1-sn-3-phosphatidylcholine (POPC) bilayer. The studied system included one cytotoxin molecule, 64 lipid molecules (32 molecules in each monolayer) and 2500 water molecules. It was found that the toxin interacted with zwitterionic bilayer formed by POPC. During first nanosecond of simulation the toxin molecule was oriented toward membrane surface by loops' basement including cytotoxin regions Cys14-Asn19 and Cys38-Ser46. This orientation was stable enough and was not changed during next 6 ns of simulation. The obtained data suggest that cytotoxin molecule cannot penetrate into membrane composed of zwitterionic lipids without some auxiliary interaction.

[Molecular dynamics of oligopeptides. A comparative study of the interactions of amino acid residues in dipeptide structures].

A comparative study of the molecular dynamics of dipeptides consisting of natural amino acid residues has been carried out. Molecular dynamics protocols were used that do not violate the principle of equidistribution of energy by degrees of freedom. Autocorrelation functions of complex exponential curves from dihedrals were used for the comparative analysis. The interactions of amino acid residues were classified by their influence on the dynamic properties of neighboring amino acid residues.

Computer modeling of binding of diverse weak toxins to nicotinic acetylcholine receptors.

Weak toxins are the "three-fingered" snake venoms toxins grouped together by having an additional disulfide in the N-terminal loop I. In general, weak toxins have low toxicity, and biological targets have been identified for some of them only, recently by detecting the effects on the nicotinic acetylcholine receptors (nAChR). Here the methods of docking and molecular dynamics simulations are used for comparative modeling of the complexes between four weak toxins of known spatial structure (WTX, candoxin, bucandin, gamma-bungarotoxin) and nAChRs. WTX and candoxin are those toxins whose blocking of the neuronal alpha7- and muscle-type nAChR has been earlier shown in binding assays and electrophysiological experiments, while for the other two toxins no such activity has been reported. Only candoxin and WTX are found here to give stable solutions for the toxin-nAChR complexes. These toxins appear to approach the binding site similarly to short alpha-neurotoxins, but their final position resembles that of alpha-cobratoxin, a long alpha-neurotoxin, in the complex with the acetylcholine-binding protein. The final spatial structures of candoxin and WTX complexes with the alpha7 neuronal or muscle-type nAChR are very similar and do not provide immediate answer why candoxin has a much higher affinity than WTX, but both of them share a virtually irreversible mode of binding to one or both these nAChR subtypes. Possible explanation comes from docking and MD simulations which predict fast kinetics of candoxin association with nAChR, no gross changes in the toxin conformation (with smaller toxin flexibility on alpha7 nAChR), while slow WTX binding to nAChR is associated with slow irreversible rearrangement both of the tip of the toxin loop II and of the binding pocket residues locking finally the toxin molecule. Computer modeling showed that the additional disulfide in the loop I is not directly involved in receptor binding of WTX and candoxin, but it stabilizes the structure of loop I which plays an important role in toxin delivery to the binding site. In summary, computer modeling visualized possible modes of binding for those weak toxins which interact with the nAChR, provided no solutions for those weak toxins whose targets are not the nAChRs, and demonstrated that the additional disulfide in loop I cannot be a sound criteria for joining all weak toxins into one group; the conclusion about the diversity of weak toxins made from computer modeling is in accord with the earlier phylogenetic analysis.

[Molecular dynamics of oligopeptides 6. A comparative study of poincare cross-section of monopeptide frames in media with different hydrophobicity].

A comparative study of the molecular dynamics of natural amino acid residues and their closest homologues and isomers was carried out. Molecular dynamics protocols not interfering with the principle of equidistribution of energy with respect to degrees of freedom were used. Poincare cross-sections, auto- and cross-correlation of complex exponential curves as a function of dihedrons were considered. The classification of dynamic properties of conformational degrees of freedom in the series of amino acid residues was carried out.

A model for short alpha-neurotoxin bound to nicotinic acetylcholine receptor from Torpedo californica: comparison with long-chain alpha-neurotoxins and alpha-conotoxins.

Short-chain alpha-neurotoxins from snakes are highly selective antagonists of the muscle-type nicotinic acetylcholine receptors (nAChR). Although their spatial structures are known and abundant information on topology of binding to nAChR is obtained by labeling and mutagenesis studies, the accurate structure of the complex is not yet known. Here, we present a model for a short alpha-neurotoxin, neurotoxin II from Naja oxiana (NTII), bound to Torpedo californica nAChR. It was built by comparative modeling, docking and molecular dynamics using 1H NMR structure of NTII, cross-linking and mutagenesis data, cryoelectron microscopy structure of Torpedo marmorata nAChR [Unwin, N., 2005. Refined structure of the nicotinic acetylcholine receptor at 4A resolution. J. Mol. Biol. 346, 967-989] and X-ray structures of acetylcholine-binding protein (AChBP) with agonists [Celie, P.H., van Rossum-Fikkert, S.E., van Dijk, W.J., Brejc, K., Smit, A.B., Sixma, T.K., 2004. Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures. Neuron 41 (6), 907-914] and antagonists: alpha-cobratoxin, a long-chain alpha-neurotoxin [Bourne, Y., Talley, T.T., Hansen, S.B., Taylor, P., Marchot, P., 2005. Crystal structure of Cbtx-AChBP complex reveals essential interactions between snake alpha-neurotoxins and nicotinic receptors. EMBO J. 24 (8), 1512-1522] and alpha-conotoxin [Celie, P.H., Kasheverov, I.E., Mordvintsev, D.Y., Hogg, R.C., van Nierop, P., van Elk, R., van Rossum-Fikkert, S.E., Zhmak, M.N., Bertrand, D., Tsetlin, V., Sixma, T.K., Smit, A.B., 2005. Crystal structure of nicotinic acetylcholine receptor homolog AChBP in complex with an alpha-conotoxin PnIA variant. Nat. Struct. Mol. Biol. 12 (7), 582-588]. In complex with the receptor, NTII was located at about 30 A from the membrane surface, the tip of its loop II plunges into the ligand-binding pocket between the alpha/gamma or alpha/delta nAChR subunits, while the loops I and III contact nAChR by their tips only in a 'surface-touch' manner. The toxin structure undergoes some changes during the final complex formation (for 1.45 rmsd in 15-25 ps according to AMBER'99 molecular dynamics simulation), which correlates with NMR data. The data on the mobility and accessibility of spin- and fluorescence labels in free and bound NTII were used in MD simulations. The binding process is dependent on spontaneous outward movement of the C-loop earlier found in the AChBP complexes with alpha-cobratoxin and alpha-conotoxin. Among common features in binding of short- and long alpha-neurotoxins is the rearrangement of aromatic residues in the binding pocket not observed for alpha-conotoxin binding. Being in general very similar, the binding modes of short- and long alpha-neurotoxins differ in the ways of loop II entry into nAChR.