Implicit solvent binding calculation

Simonson T, Carlsson J, Case DA (2004) Proton binding to proteins pKa calculations with explicit and implicit solvent models. J Am Chem Soc 126 4167-4180. 

The explicit/implicit solvent approach just described requires doing at least one simulation for each protein-ligand complex. Therefore, it is still difficult to examine the binding of a large number of compounds to a receptor. However, if one focuses on a small subset of chemical space around a lead compound, one can adopt the same approximations as described earlier in free energy calculations so that simulations on the reference systems alone can be used to predict the effects of making many modifications on a lead compound. In these calculations, no molecular dynamics simulation needs to be performed on the derivatives of a lead compound. Instead, snapshots of the reference simulations are modified... 

Simonson, T, Carlsson, J., and Case, D. A. [2004]. Proton binding to proteins pka calculations with explicit and implicit solvent mode s, Journal of the American Chemical Society 126,13, pp. 4167-4180. 

Solvation is an important parameter that influences macromolecular properties such as solubility, reaction rate equilibria, partition coefficients, enzyme-substrate, and ligand-receptor binding. In free energy calculations, solvent is represented either explicitly or implicitly. The decision of whether to use explicit or implicit solvent models in a given simulation typically depends on the available computer resources. Inclusion of explicit solvent molecules is more realistic than continuum models. 

To calculate free energies, one can often obtain relative SFEs with reasonable accuracy by means of implicit solvent models such as generalized Bom/ surface area (GB/SA).4 However, for calculating relative binding affinities of ligands to proteins or for determining structural and thermodynamic properties of macromolecules, it is important to use explicit solvent models to obtain accurate results, even though explicit solvent models are more expensive computationally than the implicit solvent models. 

Thermodynamic solvent isotope effects have been utilized to evaluate the extent to which desolvation aids ligand binding [35, 36]. While the assumptions implicit in the calculations likely make precise determination of A/fsoiv impossible, the relative role of desolvation for a series of bindings is clearly accessible (Table 5). This exercise facilitates two observations that are likely general. First, a significant fraction... 

To further speed up this approach, one can replace the expensive explicit-solvent simulations with implicit ones. Statistical mechanical theory gives the Helmholtz free energy A, apart from the scaling constant of the classical partition function that cancels out in binding energy calculations, as... 

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