Explicit-solvent approaches

In summary, the use of implicit solvation models in molecular simulations offers considerable rewards, both at conceptual and practical levels. However, compared to the more established explicit solvent approach, less is known about the domain of applicability of these models, and so extra care must be taken when using them in practice. Drawing on the analogy with the development of the empirical explicit solvent force-fields over the past 30 years, it is likely that improvements in the implicit solvent framework accompanied by accumulation of practical experience will eventually make the framework a standard approach within its reasonably well-defined domain. 

Explicit-Solvent versus Continuum-Solvent Methods. Theoretical treatments of solvation can be categorized as either explicit-solvent approaches, in which many individual solvent molecules are explicitly included, or as continuum-solvent methods, where the solvent molecules are replaced by a continuous dielectric (Section 15.22). 

Implicit and Explicit Solvent Approaches for Membrane Electrostatics. 

Another way is to reduce the magnitude of the problem by eliminating the explicit solvent degrees of freedom from the calculation and representing them in another way. Methods of this nature, which retain the framework of molecular dynamics but replace the solvent by a variety of simplified models, are discussed in Chapters 7 and 19 of this book. An alternative approach is to move away from Newtonian molecular dynamics toward stochastic dynamics. 

It is possible to go beyond the SASA/PB approximation and develop better approximations to current implicit solvent representations with sophisticated statistical mechanical models based on distribution functions or integral equations (see Section V.A). An alternative intermediate approach consists in including a small number of explicit solvent molecules near the solute while the influence of the remain bulk solvent molecules is taken into account implicitly (see Section V.B). On the other hand, in some cases it is necessary to use a treatment that is markedly simpler than SASA/PB to carry out extensive conformational searches. In such situations, it possible to use empirical models that describe the entire solvation free energy on the basis of the SASA (see Section V.C). An even simpler class of approximations consists in using infonnation-based potentials constructed to mimic and reproduce the statistical trends observed in macromolecular structures (see Section V.D). Although the microscopic basis of these approximations is not yet formally linked to a statistical mechanical formulation of implicit solvent, full SASA models and empirical information-based potentials may be very effective for particular problems. 

Essential for MD simulations of nucleic acids is a proper representation of the solvent environment. This typically requires the use of an explicit solvent representation that includes counterions. Examples exist of DNA simulations performed in the absence of counterions [24], but these are rare. In most cases neutralizing salt concentrations, in which only the number of counterions required to create an electrically neutral system are included, are used. In other cases excess salt is used, and both counterions and co-ions are included [30]. Though this approach should allow for systematic smdies of the influence of salt concentration on the properties of oligonucleotides, calculations have indicated that the time required for ion distributions around DNA to properly converge are on the order of 5 ns or more [31]. This requires that preparation of nucleic acid MD simulation systems include careful consideration of both solvent placement and the addition of ions. 

Presently, only the molecular dynamics approach suffers from a computational bottleneck [58-60]. This stems from the inclusion of thousands of solvent molecules in simulation. By using implicit solvation potentials, in which solvent degrees of freedom are averaged out, the computational problem is eliminated. It is presently an open question whether a potential without explicit solvent can approximate the true potential sufficiently well to qualify as a sound protein folding theory [61]. A toy model study claims that it cannot [62], but like many other negative results, it is of relatively little use as it is based on numerous assumptions, none of which are true in all-atom representations. 

The importance of water molecules for the structural dynamics and the functioning of ribozymes was investigated by Rhodes and co-workers. They studied non-coded RNA using a combination of explicit solvent molecular dynamics and single molecule fluorescence spectroscopy approaches (Rhodes et al 2006). 

The weakest point of our approach is the treatment of the bulk solvent. The energies derived from an implicit solvent model like IPCM are mainly based on energy calculations on gas-phase structures and effects of explicit solvent molecules are not included. 

There are certain instances where this approach may be regarded as an attractive option. For example, Cossi and Crescenzi (2003) found that accurate computation of NMR chemical shifts for alcohols, etliers, and carbonyls in aqueous solution required at least one explicit solvent shell, but that beyond that shell a continuum could be used to replace what would otherwise be a need for a much larger cluster. However, just as the strengths of the two models are combined, so are the weaknesses. A typical first shell of solvent for a small molecule may be expected to be composed of a dozen or so solvent molecules. The resulting supermolecular cluster will inevitably be characterized by a large number of accessible structures that are local minima on the cluster PES, so that statistical sampling will have to be undertaken to obtain a proper equilibrium distribution. Thus, QM methods require a substantial investment of computational resources. In addition, certain technical points require attention, e.g., how does one keep the first solvent shell from exchanging with the continuum since both, in principle, foster identical solvation interactions ... 

---