Computational studies free energy perturbation methods

Shah and Maginn carried out a Monte Carlo study of CO2 solubility in [C4mim][PF6] to compute the Henry s law constant of CO2 using the test particle insertion free energy perturbation method. The Henry s law constant for solute 2 dissolved in solvent 1, Hi,i, is defined as... 

The problems that occur when one tries to estimate affinity in terms of component terms do not arise when perturbation methods are used with simulations in order to compute potentials of mean force or free energies for molecular transformations simulations use a simple physical force field and thereby implicitly include all component terms discussed earlier. We have used the molecular transformation approach to compute binding affinities from these first principles [14]. The basic approach had been introduced in early work, in which we studied the affinity of xenon for myoglobin [11]. The procedure was to gradually decrease the interactions between xenon atom and protein, and compute the free energy change by standard perturbation methods, cf. (10). An (issential component is to impose a restraint on the... 

Single-step perturbation methods have also been applied to electrostatic processes. One study probed the dielectric properties of several proteins at a microscopic level [41,42], Test charges were inserted at many different positions within or around each protein, and a dielectric relaxation free energy was computed, which is related to a microscopic dielectric susceptibility (see Sect. 12.3). 

Cummins, P.L. Gready, J.E., Computational methods for the study of enzymic reaction mechanisms III a perturbation plus QM/MM approach for calculating relative free energies of protonation, J. Comp. Chem. 2005, 26, 561-568. 

This chapter has reviewed theoretical and practical aspects of thermodynamic perturbation and thermodynamic integration, two popular methods of extracting free energies from molecular simulations. These methods find broad application in molecular simulation studies of chemical and biochemical systems. The fundamental importance of free energy in physical and chemical processes will inspire further development and refinement of these techniques. With the increasing performance of new computer architectures,these free energy techniques will become even more powerful and versatile tools. 

Further developments of these ideas took place in computational structural biology, where nonphysical local transformations were implemented within the framework of thermodynamic cycles. These nonphysical transformations were introduced in 1981 by Warshel, who studied ionization in acidic residues in proteins pK calculations). Although the cycle included nonphysical transformations, they were not carried out by the perturbation technique. A year later Warshel used the perturbation method together with umbrella sampling to study the solvation free energy contribution to an electron transfer reaction coordinate, using two spheres for donor and acceptor in water the perturbation, however, was performed along a physical path. Warshel also modeled some enzymatic reactions that involve nonphysical processes. ... 

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