New Perturbation-Related Procedures

The perturbation and integration procedures discussed above have the advantage that in principle they are exact, and they can be applied to systems of high complexity. But, only minor chemical and structural changes can be 

Another approach, which is aimed at eliminating the number of integration steps, was proposed by van Gunsteren s group. The original idea was to expand the free energy difference F(k) — F 0) in a Taylor series in k around 

The problem remains that one is generally interested in results for X = 1, for which the typical conformations are significantly different from those of X = 0, meaning that in practice the free energy difference will not converge. In- 

To validate the LRA, Aqvist and Hansson calculated by free energy perturbation the free energy associated with charging various solutes in water and in other solvents. They found that the LRA prediction (i.e., = 

1/2) is satisfied for monovalent ionic solutes but is less accurate for dipolar ones. This conclusion agrees with earlier calculations of King and Barford, who proposed yet another method based on LRA for calculating differences in the electrostatic free energy. In their method, the difference in the electrostatic free energy for a nonphysical mutation is obtained from the energy difference at the midpoint X, = 1/2 that is, E l (k = 1) - il.s)( = 0) x.=i/2- 

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