Free energy perturbation procedure

In our simulations of histone modifying enzymes, the computational approaches centered on the pseudobond ab initio quantum mechanical/molecular mechanical (QM/MM) approach. This approach consists of three major components [20,26-29] a pseudobond method for the treatment of the QM/MM boundary across covalent bonds, an efficient iterative optimization procedure which allows for the use of the ab initio QM/MM method to determine the reaction paths with a realistic enzyme environment, and a free energy perturbation method to take account... 

The Free Energy Perturbation method provides the most accurate values of energy differences by simulations [37]. However, to our knowledge this method was only once applied to CD complexes [38], but too little information about the procedure applied, provided in this paper, precludes the assessment of its reliability. 

The PMF as a function of Xs is determined by a coupled free energy perturbation and umbrella sampling technique.5,14,16,41 The computational procedure follows two steps, although they are performed in the same simulation. The first is to use a reference potential rp to enforce the orientation polarization of the solvent system along the reaction path. A convenient choice of the reference potential, which is called mapping potential in Warshel s work,13,14,16,42 is a linear combination of the reactant and product diabatic potential energy ... 

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. 

The QM/MM minimum free energy path (QM/MM-MFEP) method (122,127, 128) is a free-energy extension to the QM/MM free energy perturbation (QM/MM-FEP) method (123). In the QM/MM- MFEP method, a sequential sampling and optimization procedure is employed in which molecular dynamics simulations are performed for the MM subsystem and geometry optimizations are performed for the QM subsystem. The QM subsystem is optimized on the PMF surface for... 

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... 

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