MD simulations of membranes

The protocols for setting up MD simulations of membrane proteins are manifold. In any case, however, one needs a pre-equilibrated bilayer, which can be retrieved from different groups around the world (e.g. Peter Tieleman, Scott Feller, Helmut Heller, Mikko Karttunen) or an individual bilayer may be generated and equilibrated with regard to the respective size and nature of the protein to be studied. 

The first simulations of fully solvated phospholipid bilayers appeared in the early 90 s. °" These works showed that atomistic MD simulations of membranes were feasible (up to hundreds of picoseconds) and represented a powerful tool to study microscopic properties of... 

Remarkable progress in both software and hardware has allowed expanding the time-scales for atomistic MD simulations of membranes by Wr orders of magnitude in two decades, from the hundreds of picoseconds reported in the first studies of fully solvated phospholipid bilayersup to microseconds in current simulations. 

A final example of the simulation of a complex system is a series of MD simulations of bilayer membranes. Membranes are crucial constituents of living organisms they are the scene for many important biological processes. Experimental data are known for model systems for example for the system sodium decanoate, decanol and water that forms smectic liquid crystalline structures at room temperature, with the lipids organized in bilayers. 

In the literature, one can find many more interesting MD studies concerning lipid bilayers with additives. In particular, a wealth of MD simulations of such systems is in the field of anaesthetics (for a review see [142]). Many anaesthetics tend to accumulate at the membrane/water interface, implying that their potencies are not related to their ability to cross the membrane. Instead, it seems to be more likely that their functioning is via binding to membrane receptors. Generally, they have an effect opposite to that of cholesterol, i.e. they increase the membrane fluidity and permeability. 

MD simulations of model membrane systems have provided a unique view of lipid interactions at a molecular level of resolution [21], Due to the inherent fluidity and heterogeneity in lipid membranes, computer simulation is an attractive tool. MD simulations allow us to obtain structural, dynamic, and energetic information about model lipid membranes. Comparing calculated structural properties from our simulations to experimental values, such as areas and volumes per lipid, and electron density profiles, allows validation of our models. With molecular resolution, we are able to probe lipid-lipid interactions at a level difficult to achieve experimentally. 

There a been a number of interesting applications of the framework developed in the studies of the simple ions were MD simulations of the quadrupolar relaxation has been performed on counterions in heterogeneous systems. Studies of a droplet of aqueous Na embedded in a membrane of carboxyl groups [54], showed that the EFG was strongly effected by the local solvent structure and that continuum models are not sufficient to describe the quadrupolar relaxation. The Stemheimer approximation was employed, which had been shown to be a good approximation for the Na ion. Again, the division into molecular contributions could be employed to rationalize the complex behavior in the EFG tensor. Similar conclusions has been drawn from MD simulation studies of ions solvating DNA... 

Ion channel studies motivated Allen et al. [47] who have developed an elegant variational formalism to compute polarization charges induced on dielectric interfaces. They solved the variational problem with a steepest descent method and applied their formulation in molecular dynamics (MD) simulations of water permeation through nanopores in a polarizable membrane [48-50], Note that the functional chosen by Allen et al. [47] is not the only formalism that can be used. Polarization free energy functionals [51-53] are more appropriate for dynamical problems, such as macromolecule conformational changes and solvation [54-57],... 

We will illustrate the coupling of protein and water dynamics using results of MD simulations of several systems, including native and MG states of human a-lactalbumin (HaLA) in aqueous solution [5], ribonuclease A (RNase) in dry and hydrated powders and glycerol solution [6,7], maltose-binding protein (MBP) in a hydrated powder [8], and bacteriorhodopsin (BR) in purple membrane (PM) stacks [9,10]. Our choice of specific systems has generally been made based on the availability of experimental data to which the simulation results can be closely compared. We have accordingly set up the systems so that the simulations are very similar to the experiments, both in terms of sample composition and thermodynamic state points (i.e., temperature and pressure). 

FIGURE 16.7 Temperature dependence of protein/lipid and water dynamical properties from MD simulations of purple membrane [9,10]. (a) MSFs of protein/lipid nonexchangeable H atoms averaged over 5 ns blocks of the trajectories, (b) Temperature dependence of the inverse of the correlation times, of the protein-water (filled circles) and lipid-water (open circles) hydrogen bond correlation functions, (c) Value of the mean-squared displacement of water O atoms at f = 100 ps. 

Shao PH, Dal-Cin MM, Guiver MD, Kumar A. Simulation of membrane-based COj capture in a coal-fired power plant. JMembrSci 2013 427 451 59. 

As translocation always involves a dynamic process, which cannot easily be studied by mere experimental techniques, above all, the application of long-term MD simulations should be implemented into the whole process of drug discovery and development. Due to significant increase in compnitational power and improvements in parallelization techniques, nowadays simulations of membrane transport proteins may stretch up to microseconds - that is, to physiologically relevant time scales. In this review we are describing the theory and methodology related to computational techniques used in the modeling of transporters and we will outline the recent developments in the field of ABC transporters and neurotransmitter transporters. 

U. Essmann, L. Perera, and M.L. Berkowitz. The origin of the hydration interaction of lipid bilayers from MD simulation of dipalmitoylphosphatidylcholine membranes in gel and liquid crystalline phases. Langmuir, 11 (1995)4519-4531. 

MD simulations were carried out in the NPT ensemble, with the temperature at 310 K and pressure set at 1 atm. MD simulation of each vesicle system was conducted for 1 ps, although the MD run of the flat membrane was performed for only 300 ns. 

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