Solvents molecular dynamics development

To enable an atomic interpretation of the AFM experiments, we have developed a molecular dynamics technique to simulate these experiments [49], Prom such force simulations rupture models at atomic resolution were derived and checked by comparisons of the computed rupture forces with the experimental ones. In order to facilitate such checks, the simulations have been set up to resemble the AFM experiment in as many details as possible (Fig. 4, bottom) the protein-ligand complex was simulated in atomic detail starting from the crystal structure, water solvent was included within the simulation system to account for solvation effects, the protein was held in place by keeping its center of mass fixed (so that internal motions were not hindered), the cantilever was simulated by use of a harmonic spring potential and, finally, the simulated cantilever was connected to the particular atom of the ligand, to which in the AFM experiment the linker molecule was connected. 

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]. 

Equation (4-5) can be directly utilized in statistical mechanical Monte Carlo and molecular dynamics simulations by choosing an appropriate QM model, balancing computational efficiency and accuracy, and MM force fields for biomacromolecules and the solvent water. Our group has extensively explored various QM/MM methods using different quantum models, ranging from semiempirical methods to ab initio molecular orbital and valence bond theories to density functional theory, applied to a wide range of applications in chemistry and biology. Some of these studies have been discussed before and they are not emphasized in this article. We focus on developments that have not been often discussed. 

This potential was developed to ensure that the molecules inside the sphere never escape and maintain a fully solvated system during molecular dynamics. Here, es, Rs, ew and Rw are the van der Waals constants for the solvent and the wall and rj is the distance between the molecule i and the center of the water sphere, Ro is the radius of the sphere. The quantities A, B and Rb are determined by imposing the condition that W and dW/dr, vanish at r, = Ro. The restraining potential W is set to zero for r, < R0. The van der Waals parameters Es, ew, Rs and Rw can also be specifically defined for different solvents. The constants Awaii and Cwan are computed using a well depth of es = ew = 0.1 kcal and the radius of Rs = Rw = 1.25 A. For the other set of simulations, especially for the hydride ion transfer, we applied periodic boundary conditions by using a spherical boundary shell of 10.0 A of TIP3P40 water to cover the edges of the protein. 

An interesting combined use of discrete molecular and continuum techniques was demonstrated by Floris et al.181,182 They used the PCM to develop effective pair potentials and then applied these to molecular dynamics simulations of metal ion hydration. Another approach to such systems is to do an ab initio cluster calculation for the first hydration shell, which would typically involve four to eight water molecules, and then to depict the remainder of the solvent as a continuum. This was done by Sanchez Marcos et al. for a group of five cations 183 the continuum model was that developed by Rivail, Rinaldi et al.14,108-112 (Section III.2.ii). Their results are compared in Table 14 with those of Floris et al.,139 who used a similar procedure but PCM-based. In... 

Considering these results and the contributions by Broos [125], Watanabe [126], and Ueji [55, 77], it may be concluded that the relation between enzyme flexibility and enanhoselective performance in organic solvents is now firmly established. Molecular dynamic simulations on the flexibility of subtilisin and the mobility of bound water molecules in carbon tetrachloride corroborate the idea that organic solvents reduce molecular flexibility via interactions at specific binding sites [127]. Whether predictive tools can be developed on the basis of this knowledge remains to be seen. 

A major criticism of all this work is the treatment of the solvent as hydrodynamic continuum. To study the hydrodynamic repulsion of particles requires either molecular dynamics calculations or time-dependent liquid theories to be applied. It will be most interesting to see how the analysis using kinetic theory develops (see, for instance, Cukier et al. [454]). 

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