Molecular dynamics simulation bilayers

The first molecular dynamics simulations of a lipid bilayer which used an explicit representation of all the molecules was performed by van der Ploeg and Berendsen in 1982 [van dei Ploeg and Berendsen 1982]. Their simulation contained 32 decanoate molecules arranged in two layers of sixteen molecules each. Periodic boundary conditions were employed and a xmited atom force potential was used to model the interactions. The head groups were restrained using a harmonic potential of the form ... 

This chapter has given an overview of the structure and dynamics of lipid and water molecules in membrane systems, viewed with atomic resolution by molecular dynamics simulations of fully hydrated phospholipid bilayers. The calculations have permitted a detailed picture of the solvation of the lipid polar groups to be developed, and this picture has been used to elucidate the molecular origins of the dipole potential. The solvation structure has been discussed in terms of a somewhat arbitrary, but useful, definition of bound and bulk water molecules. 

The rapid rise in computer speed over recent years has led to atom-based simulations of liquid crystals becoming an important new area of research. Molecular mechanics and Monte Carlo studies of isolated liquid crystal molecules are now routine. However, care must be taken to model properly the influence of a nematic mean field if information about molecular structure in a mesophase is required. The current state-of-the-art consists of studies of (in the order of) 100 molecules in the bulk, in contact with a surface, or in a bilayer in contact with a solvent. Current simulation times can extend to around 10 ns and are sufficient to observe the growth of mesophases from an isotropic liquid. The results from a number of studies look very promising, and a wealth of structural and dynamic data now exists for bulk phases, monolayers and bilayers. Continued development of force fields for liquid crystals will be particularly important in the next few years, and particular emphasis must be placed on the development of all-atom force fields that are able to reproduce liquid phase densities for small molecules. Without these it will be difficult to obtain accurate phase transition temperatures. It will also be necessary to extend atomistic models to several thousand molecules to remove major system size effects which are present in all current work. This will be greatly facilitated by modern parallel simulation methods that allow molecular dynamics simulations to be carried out in parallel on multi-processor systems [115]. 

Thus the formation of tilted analogues of the smectic A phases, i.e. monolayer Cl and bilayer C2, is possible for mesogens with relatively large electric quadrupoles. In the case of strongly sterically asymmetric molecules (e.g., zigzag shaped or dumbell shaped molecules, Fig. 3b) these quadrupolar interactions may be steric in origin. From this point of view observation of molecular tilt in the molecular dynamics simulations for a one-layer film of DOBAMBC in the absence of electrostatic interactions is not so surprising [106]. 

Studies of the effect of permeant s size on the translational diffusion in membranes suggest that a free-volume model is appropriate for the description of diffusion processes in the bilayers [93]. The dynamic motion of the chains of the membrane lipids and proteins may result in the formation of transient pockets of free volume or cavities into which a permeant molecule can enter. Diffusion occurs when a permeant jumps from a donor to an acceptor cavity. Results from recent molecular dynamics simulations suggest that the free volume transport mechanism is more likely to be operative in the core of the bilayer [84]. In the more ordered region of the bilayer, a kink shift diffusion mechanism is more likely to occur [84,94]. Kinks may be pictured as dynamic structural defects representing small, mobile free volumes in the hydrocarbon phase of the membrane, i.e., conformational kink g tg ) isomers of the hydrocarbon chains resulting from thermal motion [52] (Fig. 8). Small molecules can enter the small free volumes of the kinks and migrate across the membrane together with the kinks. 

Gumbart, J. Wang, Y. Aksimentiev, A. Tajkhorshid, E. Schulten, K., Molecular dynamics simulations of proteins in lipid bilayers, Curr. Opin. Struct. Biol. Aug 2005,15, 423—A3. ... 

Figure 1 (Plate 1). A molecular view of a small section of a flat lipid bilayer generated by molecular dynamics simulations. The bilayers are composed of l-stearoyl-2-docosa-hexaenoyl-5M-g]ycero-3-phosphatidylcholine lipids, i.e. the sn 1 chain is 18 C atoms long and the sn2 chain has 22 carbons, including six cis double bonds. The hydrophobic core is in the centre of the picture, and the hydrated head-group regions are both on top and bottom of the view graph. The head group is zwitterionic and no salt has been added. From [102], Reproduced by permission of the American Physical Society. Copyright (2003)...

The strong point of molecular dynamic simulations is that, for the particular model, the results are (nearly) exact. In particular, the simulations take all necessary excluded-volume correlations into account. However, still it is not advisable to have blind confidence in the predictions of MD. The simulations typically treat the system classically, many parameters that together define the force field are subject to fine-tuning, and one always should be cautious about the statistical certainty. In passing, we will touch upon some more limitations when we discuss more details of MD simulation of lipid systems. We will not go into all the details here, because the use of MD simulation to study the lipid bilayer has recently been reviewed by other authors already [31,32]. Our idea is to present sufficient information to allow a critical evaluation of the method, and to set the stage for comparison with alternative approaches. 

Lindahl, E. and Edholm, O. (2000). Spatial and energetic-entropic decomposition of surface tension in lipid bilayers from molecular dynamics simulations, J. Chem. Phys., 113, 3882-3893. 

Venable, R. M., Brooks, B. R. and Pastor, R. W. (2000). Molecular dynamics simulations of gel phase lipid bilayers in constant pressure and constant surface area ensembles, J. Chem. Phys., 112, 4822-4832. 

Hyvonen, M. T., Rantala, T. T. and Ala-Korpela, M. (1997). Structure and dynamic properties of diunsaturated l-palmitoyl-2-linoleoyl-,sM-glycero-3-phosphatidylcholine lipid bilayer from molecular dynamics simulation, Biophys. J., 73, 2907-2923. 

Chiu, S. W., Clark, M., Balaji, V., Subramaniam, S., Scott, H. L. and Jakobsson, E. (1995). Incorporation of surface tension into molecular dynamics simulation of an interface a fluid phase lipid bilayer membrane, Biophys. J., 69,1230-1245. 

Tieleman, D. P. and Berendsen, H. J. C. (1996). Molecular dynamics simulations of a fully hydrated dipalmitoylphosphatidylcholine bilayer with different macroscopic boundary conditions and parameters, J. Chem. Phys., 105, 4871 —4880. 

Berger, O., Edholm, O. and Jahnig F. (1997). Molecular dynamics simulations of a fluid bilayer of dipalmitoylphosphatidylcholine at full hydration, constant pressure and constant temperature, Biophys. J., 72, 2002-2013. 

Tu, K., Tobias, D. J. and Klein M. L. (1995). Constant pressure and temperature molecular dynamics simulation of a fully hydrated liquid crystal phase dipalmitoylphosphatidylcholine bilayer, Biophys. J., 69, 2558-2562. 

Leermakers, F. A. M., Rabinovich, A. L. and Balabaev, N. K. (2003). Self-consistent field modeling of hydrated unsaturated lipid bilayers in the liquid-crystal phase and comparison to molecular dynamics simulations, Phys. Rev. E, 67, 011910. 

Xiang, T. X. and Anderson, B. D. (1999). Molecular dissolution processes in lipid bilayers a molecular dynamics simulation, J. Chem. Phys., 110, 1807-1818. 

Bassolino-Klimas, D., Alper, H. E. and Stouch, T. R. (1993). Solute diffusion in lipid bilayer membranes an atomic level study by molecular dynamics simulation,... 

Fig. 8 Proposed model for gramicidin S in a membrane according to the orientational constraints obtained from and N-NMR. The upright backbone alignment (r 80°) and slant of the /3-sheets (p -45°) are compatible with the formation of an oligomeric /3-barrel that is stabilized by hydrogen bonds (dotted lines). A The oligomer is depicted sideways from within the lipid bilayer interior (showing only backbone atoms for clarity, but with hydrophobic side chains added to one of the monomers). Atomic coordinates of GS were taken from a monomeric structure [4], and the two DMPC lipid molecules are drawn to scale (from a molecular dynamics simulation coordinate file). The bilayer cross-section is coloured yellow in its hydrophobic core, red in the amphiphilic regions, and light blue near the aqueous surface. B Illustrates a top view of the putative pore, although the number of monomers remains speculative...

The Guy open conformation model docked structure was minimized in vacuo followed by a 1-ns molecular dynamics simulation of the complex embedded in a phosphatidylethanolamine (POPE) lipid bilayer. Adjustments were made to the model, and simulations were repeated so that very little movement occurred during the hnal iterations. Similar methods were used to dock the two domains in transitional and resting states. However, these results are more tenuous as little experimental data is available. In particular, the position of the S4-S5 linker and its role in opening and closing the pore are uncertain. The supplemental movie accompanying reference 36 illustrates the open-to-close-to-open cycle resulting from the simulations. 

Zhang, Z., Bhide, S.Y., Berkowitz, M.L. Molecular dynamics simulations of bilayers containing mixtures of sphingomyelin with cholesterol and phosphatidylcholine with cholesterol. J. Phys. Chem. B 2007, 111, 12888-97. 

Khelashvili, G.A., Scott, H.L. Combined Monte Carlo and molecular dynamics simulation of hydrated 18 0 sphingomyelin-cholesterol lipid bilayers. J. Chem. Phys. 2004, 120, 9841-7. 

Leontiadou, H., Mark, A.E., Marrink, S.J. Molecular dynamics simulations of hydrophilic pores in lipid bilayers. Biophys. J. 2004, 86, 2156-64. 

Tolpekina, T.V., den Otter, W.K., Briels, W.J. Nucleation free energy of pore formation in an amphiphilic bilayer studied by molecular dynamics simulations. J. Chem. Phys. 2004, 121, 12060-6. 

Kucerka, N., Perlmutter, J.D., Pan, J., Tristram-Nagle, S., Katsaras, J., Sachs, J.N. The effect of cholesterol on short- and long-chain monounsaturated lipid bilayers as determined by molecular dynamics simulations and X-ray scattering. Biophys. J. 2008, 95, 2792-805. 

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