Free-energy perturbation technique

In this study, identification of the critical atomic and molecular determinants pertaining to the mechanism of dihydrofolate to tetrahydrofolate reduction was achieved by (i) ab initio quantum mechanics, (ii) molecular mechanics, and (iii) free energy perturbation techniques. For the first time, the complete free energy profile was calculated for the proton transfer from Asp27 of the enzyme E. Coli DHFR to the N5 position of the dihydropterin moiety of the substrate dihydrofolate. In addition, the free... 

A widely-used alternative is the free energy perturbation technique (FEP),9"11,72"74 which will be discussed for the Gibbs free energy G. It involves a thermodynamic cycle such as the following, in which X and Y are two different molecules that are undergoing solvation in a particular solvent ... 

In order to calculate AGciay or AGsoln (Eq. [8] and [9]) with the free energy perturbation technique, it is necessary to compute and sum the relative free energy differences between adjacent mutation steps. A procedure that can be used for this purpose is readily derived from standard statistical thermodynamic formulae. 

In all simulations of clay mineral systems we apply periodic boundary conditions at constant pressure and temperature (constant NPT), This allows the system volume to change freely at 100 kPa (1 bar) external pressure and 298 K. Furthermore we employ Ewald summation to compute both electrostatic potentials and dispersive van der Waals interactions, and the simulations are fully dynamic, using the Discover module and Insight II graphical user interface of the MSI molecular modeling suite (MSI, 1997). The free energy perturbation technique is not implemented in this software per se so that many of the aforementioned calculations have to be performed with spreadsheet software (e.g., Microsoft Excel). 

It is sometimes desirable not only to predict the struaure of a potentially active ligand, but also to perform rigorous quantitative calculations on the proposed ligand-receptor complex. Two major computational approaches have been used for such predictions interaction energy calculations and free energy perturbation techniques. Such calculations should take into account solvation effects because this is often a driving force in the interaction. 

Thus, one may fairly compare the free-energy perturbation technique with the molecular mechanics methods in order to have a correct assessment of the various advantages associated with the estimation of the relative binding affinities of COX-2, inhibitors. 

It is worth to note that the N7<->N8 tautomerism is expected to play a key role in the determination of the biological activity of this molecule. Thus, high level ab initio calculations coupled to free energy perturbation techniques and... 

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