Ion channel simulation

The self-consistent nature of the simulation approaches described in this chapter requires frequent solutions of Poisson s equation the potential profiles from one step to the next are very similar to each other because the changes in the charge distribution between two consecutive solutions are very small (but very important for the particle dynamics). The current potential profile can thus generally be used as a good initial guess for the next solution, which makes iterative methods a natural choice within the framework of self-consistent simulation programs. In addition, memory issues (other than pure performance) make the choice of iterative methods appealing in the field of ion channel simulations. 

Whereas the main challenge for the first bilayer simulations has been to obtain stable bilayers with properties (e.g., densities) which compare well with experiments, more and more complex problems can be tackled nowadays. For example, lipid bilayers were set up and compared in different phases (the fluid, the gel, the ripple phase) [67,68,76,81]. The formation of large pores and the structure of water in these water channels have been studied [80,81], and the forces acting on lipids which are pulled out of a membrane have been measured [82]. The bilayer systems themselves are also becoming more complex. Bilayers made of complicated amphiphiles such as unsaturated lipids have been considered [83,84]. The effect of adding cholesterol has been investigated [85,86]. An increasing number of studies are concerned with the important complex of hpid/protein interactions [87-89] and, in particular, with the structure of ion channels [90-92]. 

The major drawback of these models, however, is their lack of a clear reference between model components and constituent parts of the biological system (e.g. structures like ion channels, transporter proteins, receptors, etc.). These models, therefore, do not permit the simulation of patho-physiological detail, such as the series of events that follows a reduction in oxygen supply to the cardiac muscle and, ultimately, causes serious disturbances in heart rhythm. 

The QM/MM and ab initio methodologies have just begun to be applied to challenging problems involving ion channels [73] and proton motion through them [74]. Reference [73] utilizes Hartree-Fock and DFT calculations on the KcsA channel to illustrate that classical force fields can fail to include polarization effects properly due to the interaction of ions with the protein, and protein residues with each other. Reference [74] employs a QM/MM technique developed in conjunction with Car-Parrinello ab initio simulations [75] to model proton and hydroxide ion motion in aquaporins. Due to the large system size, the time scale for these simulations was relatively short (lOps), but the influences of key residues and macrodipoles on the short time motions of the ions could be examined. 

Bliznyuk, A. A. Rendell, A. P., Electronic effects in biomolecular simulations investigations of the KcsA potassium ion channel, J. Phys. Chem. B 2004,108, 13866-13873... 

Marco Saraniti, Shela Aboud, and Robert Eisenberg, The Simulation of Ionic Charge Transport in Biological Ion Channels An Introduction to Numerical Methods. 

Acetylcholine receptors. There are numerous receptors for ACh (Fig. 12—10), of which the major subtypes are nicotinic and muscarinic subtypes of cholinergic receptors. Classically, muscarinic receptors are simulated by the mushroom alkaloid muscarine and nicotinic receptors by the tobacco alkaloid nicotine. Nictotinic receptors are all ligand-gated, rapid-onset, and excitatory ion channels, which are blocked by curare. Muscarinic receptors, by contrast, are G protein—linked, can be excitatory or inhib-... 

The interactions of several peptides with phospholipids have been studied by computer simulation. Emphasis has been given to several aspects of protein-phospholipid interactions, including the way of association and orientational preference of peptides in contact with a bilayer, the effect of phospholipids on the preference and stability of helical conformations, and the effect of the inserted peptide on the structure and dynamics of the phospholipids. These investigations have been extended to bundles of helices and even whole pore-forming proteins. In particular, the simulation of ion channels and of peptides with antimicrobial action has attracted a great deal of attention in theoretical studies. 

Simulations of Pore-forming Peptides and ofthe Diffusion of Ions Through Ion Channels... 

The simulation of ion channels and other pore-forming peptides and proteins at atomic detail is nowadays also possible. With the increase in computational power, these complex systems have attracted much more interest, and several simulations have been reported. Very often, only the transmembrane segments of the channel-forming proteins are included in the simulation to reduce the size and complexity of the system. The simulated systems range from synthetic model ion channels to a bacterial porine protein. 

To investigate numerically the dependence of exocytosis probability on ion channel clustering and to test our theoretical results, we carried out numerical simulations on a system of identical and independent two-state channels. A set of dwell times for a single channel in shut and open states was generated with the help of a source equation ... 

The properties of this X-ray beam are in a good agreement with the synchrotron radiation emitted by the trapped electrons undergoing betatron oscillations in an ion channel, as described by numerical simulations. The... 

Standard molecular mechanics (MM) force fields have been developed that provide a good description of protein structure and dynamics,21 but they cannot be used to model chemical reactions. Molecular dynamics simulations are very important in simulations of protein folding and unfolding,22 an area in which they complement experiments and aid in interpretation of experimental data.23 Molecular dynamics simulations are also important in drug design applications,24 and particularly in studies of protein conformational changes,25,26 simulations of the structure and function of ion channels and other membrane proteins,27-29 and in studies of biological macromolecular assemblies such as F-l-ATPase.30... 

In any case, because ion scattering is strongly affected by the thermal vibrations of surface atoms, experimental data must be compared to Monte-Carlo simulations for model surfaces to achieve quantitative results. The available data base for structure-fitting is rather small compared to electron spectroscopies, so the sensitivity to structural parameters is sometimes limited. But when the surface structure is close to the bulk structure, ion channeling data can be strongly sensitive to small variations in structural parameters. 

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