Free energy simulations, types

Free energy simulations are a useful means of quantitating whether the free energy and not simply the energy is shifting in the predicted manner for the mutant (see Chapter 9). The difference in the free energy changes upon reduction between a wild-type and a mutant, AAG = AG — AG, where the asterisk indicates the mutant, can be calculated in two ways via the thennodynamic cycle shown in Scheme 2,... 

Free energy simulation methods have been applied to a wide range of problems in chemistry and biology. These studies have been surveyed in several excellent reviews. " The sections that follow review the more recent literature and describe how free energy simulation methods have been applied to various problems. Broadly speaking, two types of molecular phenomena have been studied using free energy simulations (1) solvation and (2) molecular association. These are discussed separately below. 

Free Energy Calculations Methods and Applications Free Energy Perturbation Calculations Free Energy Simulations Hydrogen Bonding 1 Hydrogen Bonding 2 Molecular Dynamics DNA Molecular Dynamics Simulations of Nucleic Acids Molecular Dynamics Techniques and Applications to Proteins Nucleic Acid Force Fields Poisson-Boltzmann Type Equations Numerical Methods Protein Force Fields. 

Given that these are highly concentrated solutions containing a large number of counterions, the coordination number may also be sensitive to the type of counterions. To better understand this effect, metadynamics free energy simulation was used to study the effect that... 

While simulations reach into larger time spans, the inaccuracies of force fields become more apparent on the one hand properties based on free energies, which were never used for parametrization, are computed more accurately and discrepancies show up on the other hand longer simulations, particularly of proteins, show more subtle discrepancies that only appear after nanoseconds. Thus force fields are under constant revision as far as their parameters are concerned, and this process will continue. Unfortunately the form of the potentials is hardly considered and the refinement leads to an increasing number of distinct atom types with a proliferating number of parameters and a severe detoriation of transferability. The increased use of quantum mechanics to derive potentials will not really improve this situation ab initio quantum mechanics is not reliable enough on the level of kT, and on-the-fly use of quantum methods to derive forces, as in the Car-Parrinello method, is not likely to be applicable to very large systems in the foreseeable future. 

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. 

Reactor types modeled A, stoichiometric conversion B, equiUbrium/free-energy minimization, continuous stirred tank, and plug flow C, reactive distillation. Some vendors have special models for special reactions also, private company simulators usually have reactors of specific interest to their company. 

Thermodynamic perturbation theory represents a powerful tool for evaluating free energy differences in complex molecular assemblies. Like any method, however, FEP has limitations of its own, and particular care should be taken not only when carrying out this type of statistical simulations, but also when interpreting their results. We summarize in a number of guidelines the important concepts and features of FEP calculations developed in this chapter ... 

---