Simulations, solvent effects

G. Ramachandran and T. Schlick. Solvent effects on supercoiled DNA dynamics explored by Langevin dynamics simulations. Phys. Rev. E, 51 6188-6203, 1995. 

Although there are examples of enzymes which maintain their catalytic activity even when ciystallized, they normally work in their natural (i.e., aqueous) environment. This is the reason why the majority of the simulations are carried out applying a technique that accounts for solvent effects. But what is the effect of a solvent ... 

Yun-Yu S, W Lu and W F van Gunsteren 1988. On the Approximation of Solvent Effects on Conformation and Dynamics of Cyclosporin A by Stochastic Dynamics Simulation Teclmiqi Molecular Simulation 1 369-383. 

Ha S, J Gao, B Tidor, J W Brady and M Karplus 1991. Solvent Effect on the Anomeric Equilibrium in d Glucose A Free Eneigy Simulation Analysis. Journal of the American Chemical Sod. ty 113 1553-1557... 

Solvents exert their influence on organic reactions through a complicated mixture of all possible types of noncovalent interactions. Chemists have tried to unravel this entanglement and, ideally, want to assess the relative importance of all interactions separately. In a typical approach, a property of a reaction (e.g. its rate or selectivity) is measured in a laige number of different solvents. All these solvents have unique characteristics, quantified by their physical properties (i.e. refractive index, dielectric constant) or empirical parameters (e.g. ET(30)-value, AN). Linear correlations between a reaction property and one or more of these solvent properties (Linear Free Energy Relationships - LFER) reveal which noncovalent interactions are of major importance. The major drawback of this approach lies in the fact that the solvent parameters are often not independent. Alternatively, theoretical models and computer simulations can provide valuable information. Both methods have been applied successfully in studies of the solvent effects on Diels-Alder reactions. 

Studies on solvent effects on the endo-exo selectivity of Diels-Alder reactions have revealed the importance of hydrogen bonding interactions besides the already mentioned solvophobic interactions and polarity effects. Further evidence of the significance of the former interactions comes from computer simulations" and the analogy with Lewis-acid catalysis which is known to enhance dramatically the endo-exo selectivity (Section 1.2.4). 

A number of antioxidants have been accepted by the FDA as indirect additives for polymers used in food appHcations. Acceptance is deterrnined by subchronic or chronic toxicity in more than one animal species and by the concentration expected in the diet, based on the amount of the additive extracted from the polymer by typical foods or solvents that simulate food in their extractive effects. Only materials of insignificant risk to the consumer are regulated by the FDA for use in plastics contacted by food stuffs. 

The integral equation method is free of the disadvantages of the continuum model and simulation techniques mentioned in the foregoing, and it gives a microscopic picture of the solvent effect within a reasonable computational time. Since details of the RISM-SCF/ MCSCF method are discussed in the following section we here briefly sketch the reference interaction site model (RISM) theory. 

The effects of confinement due to matrix species on the PMF between colloids is very well seen in Fig. 1(c). At a small matrix density, only the solvent effects contribute to the formation of the PMF. At a higher matrix density, the solvent preserves its role in modulating the PMF however, there appears another scale. The PMF also becomes modulated by matrix species additional repulsive maxima and attractive minima develop, reflecting configurations of colloids separated by one or two matrix particles or by a matrix particle covered by the solvent layer. It seems very difficult to simulate models of this sort. However, previous experience accumulated in the studies of bulk dispersions and validity of the PY closure results gives us confidence that the results presented are at least qualitatively correct. 

Both of these substitution pathways in MeCN solution have been simulated using the Onsager model (Tables IV and V). Whereas pathway b is favored in the gas phase, inclusion of solvent effects in the calculations causes pathway a to be energetically favored. Substitution of Cl via pathway a is now 1.6 kcal/mol more favorable. In addition, TS(X)/TS(Pyr) calculations (Scheme 15) for the OMe (40) and OSiMes (41) cations have been performed. TS(X) of both 40 and 41 remain significantly disfavored (+66.9 kcal/mol and +46.6 kcakmol, respectively), thus indicating that pathway b should be preferred in MeCN.Tliese calculations are in complete agreement with experimental observations. 

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]. 

Levy (Chapter 6) has also explored the use of supercomputers to study detailed properties of biological macromolecule that are only Indirectly accessible to experiment, with particular emphasis on solvent effects and on the Interplay between computer simulations and experimental techniques such as NMR, X-ray structures, and vltratlonal spectra. The chapter by Jorgensen (Chapter 12) summarizes recent work on the kinetics of simple reactions In solutions. This kind of calculation provides examples of how simulations can address questions that are hard to address experimentally. For example Jorgensen s simulations predicted the existence of an Intermediate for the reaction of chloride Ion with methyl chloride In DMF which had not been anticipated experimentally, and they Indicate that the weaker solvation of the transition state as compared to reactants for this reaction In aqueous solution Is not due to a decrease In the number of hydrogen bonds, but rather due to a weakening of the hydrogen bonds. 

The use of computer simulations to study internal motions and thermodynamic properties is receiving increased attention. One important use of the method is to provide a more fundamental understanding of the molecular information contained in various kinds of experiments on these complex systems. In the first part of this paper we review recent work in our laboratory concerned with the use of computer simulations for the interpretation of experimental probes of molecular structure and dynamics of proteins and nucleic acids. The interplay between computer simulations and three experimental techniques is emphasized (1) nuclear magnetic resonance relaxation spectroscopy, (2) refinement of macro-molecular x-ray structures, and (3) vibrational spectroscopy. The treatment of solvent effects in biopolymer simulations is a difficult problem. It is not possible to study systematically the effect of solvent conditions, e.g. added salt concentration, on biopolymer properties by means of simulations alone. In the last part of the paper we review a more analytical approach we have developed to study polyelectrolyte properties of solvated biopolymers. The results are compared with computer simulations. 

Amides, alkaline hydrolysis, 215 Anharmonic systems, direct evaluation of quantum time-correlation functions, 93 Apollo DSP—160, CHARMM performance, 129/ simulations, solvent effects, 83... 

Sudholt W, Staib A, Sobolewski AL, Domcke W (2000) Molecular-dynamics simulations of solvent effects in the intramolecular charge transfer of 4-(N, N-dimethylamino) benzonitrile. Phys Chem Chem Phys 2(19) 4341-4353... 

Quantum chemical methods are well established, accepted and of high potential for investigation of inorganic reaction mechanisms, especially if they can be applied as a fruitful interplay between theory and experiment. In the case of solvent exchange reactions their major deficiency is the limited possibility of including solvent effects. We demonstrated that with recent DFT-and ab initio methods, reaction mechanisms can be successfully explored. To obtain an idea about solvent effects, implicit solvent models can be used in the calculations, when their limitations are kept in mind. In future, more powerful computers will be available and will allow more sophisticated calculations to be performed. This will enable scientists to treat solvent molecules explicitly by ab initio molecular dynamics (e.g., Car-Parrinello simulations). The application of such methods will in turn complement the quantum chemical toolbox for the exploration of solvent and ligand exchange reactions. 

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