Solvation effects molecular modeling

Hydrogen-bonded clusters are an important class of molecular clusters, among which small water clusters have received a considerable amount of attention [148, 149]. Solvated cluster ions have also been produced and studied [150, 151]. These solvated clusters provide ideal model systems to obtain microscopic infonnation about solvation effect and its influence on chemical reactions. 

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 simulation of molecules in solution can be broken down into two categories. The first is a list of elfects that are not defined for a single molecule, such as diffusion rates. These types of effects require modeling the bulk liquid as discussed in Chapters 7 and 39. The other type of effect is a solvation effect, which is a change in the molecular behavior due to the presence of a solvent. This chapter addresses this second type of effect. 

The second group of studies tries to explain the solvent effects on enantioselectivity by means of the contribution of substrate solvation to the energetics of the reaction [38], For instance, a theoretical model based on the thermodynamics of substrate solvation was developed [39]. However, this model, based on the determination of the desolvated portion of the substrate transition state by molecular modeling and on the calculation of the activity coefficient by UNIFAC, gave contradictory results. In fact, it was successful in predicting solvent effects on the enantio- and prochiral selectivity of y-chymotrypsin with racemic 3-hydroxy-2-phenylpropionate and 2-substituted 1,3-propanediols [39], whereas it failed in the case of subtilisin and racemic sec-phenetyl alcohol and traws-sobrerol [40]. That substrate solvation by the solvent can contribute to enzyme enantioselectivity was also claimed in the case of subtilisin-catalyzed resolution of secondary alcohols [41]. 

In addition to heterocycles, other molecular systems have attracted theoretical attention with respect to prediction of tautomeric equilibria and solvation effects thereon. The most commonly studied example in this class is the equilibrium between formamide and formamidic acid, discussed in the next section. In addition, some continuum modeling of solvation effects on keto/enol equilibria have appeared these are presented in section 4.2.2.2. We note that the equilibrium... 

Effects of solvation on zwitterion formation between methylamine and fom-aldehydewere studied by various solvation methods. The SM2/AM1 model predicted the expected zwitterionc minimum while SM3/PM3 failed to do so [127]. Calculations were performed with the use of AMSOL to account for solvation effects in the study of molecular properties and pharmacokinetic behavior of ce-tirizine, a zwitterionic third-generation antihistaminic. Results indicated that the folded conformation remains of low energy not only in vacuo but also in water solution [128]. 

Unfortunately specific solvation effects are very difficult to understand, although molecular mechanics simulations have recently gone some way towards modelling complexation phenomena... 

Nevertheless, the concept of spatial dispersion provides a general background for a qualitative understanding of those solvation effects which are beyond the scope of local continuum models. The nonlocal theory creates a bridge between conventional and well developed local approaches and explicit molecular level treatments such as integral equation theory, MC or MD simulations. The future will reveal whether it can survive as a computational tool competitive with these popular and more familiar computational schemes. 

Recent perspective concerning DC models of solvation has been provided by molecular-level theories and simulations [18,19,27], Such studies, for example, draw attention to the importance of departures from the homogeneous, spatially local models discussed above, and help to elucidate the nature of effective molecular cavities. Examples of these effects will be included in the specific results illustrated in Section 3.5.5, Comparison of s Based on Molecular-level and Continuum Models. 

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