Ensemble free energy calculations

Free energy calculations rely on the following thermodynamic perturbation theory [6-8]. Consider a system A described by the energy function = 17 + T. 17 = 17 (r ) is the potential energy, which depends on the coordinates = (Fi, r, , r ), and T is the kinetic energy, which (in a Cartesian coordinate system) depends on the velocities v. For concreteness, the system could be made up of a biomolecule in solution. We limit ourselves (mostly) to a classical mechanical description for simplicity and reasons of space. In the canonical thermodynamic ensemble (constant N, volume V, temperature T), the classical partition function Z is proportional to the configurational integral Q, which in a Cartesian coordinate system is... 

UU is the Hamiltonian difference (the perturbation) the angle brackets represent a canonical ensemble average performed on an equilibrated system designated by the subscript. Usually the kinetic component of the Hamiltonian is not included in the free energy calculation, and A- //, n can be replaced by the potential energy difference AU = Ui - U0. 

Finally, in Sect. 7.6, we have discussed how various free energy calculation methods can be applied to determine free energies of ensembles of pathways rather than ensembles of trajectories. In the transition path sampling framework such path free energies are related to the time correlation function from which rate constants can be extracted. Thus, free energy methods can be used to study the kinetics of rare transitions between stable states such as chemical reactions, phase transitions of condensed materials or biomolecular isomerizations. 

A solvated MD simulation is performed to determine an ensemble of conformations for the molecule of interest. This ensemble is then used to calculate the terms in this equation. Vm is the standard molecular mechanics energy for each member of the ensemble (calculated after removing the solvent water). G PB is the solvation free energy calculated by numerical integration of the Poisson-Boltzmann equation plus a simple surface energy term to estimate the nonpolar free energy contribution. T is the absolute temperature. S mm is the entropy, which is estimated using... 

An alternative approach to free energy calculations is the thermodynamic integration (TI) method,18 20 which considers the ensemble average of the first derivative of the hybrid potential with respect to A at various values of A... 

Blondel. A. 2004. Ensemble Variance in Free Energy Calculations by Thermodynamic Integration Theoiy. Optimal Alchemical Path, and Practical Solution. J. Compul. Chem., 25, 985. 

This replica-trick method was used in the Refs. [60,61] for the polymer network free energy calculation. For averaging of Z"-value over the ensemble of realizations the probability distribution should be chosen. The authors of Refs. [60,61] have used the condition of the thermodynamical equilibrium for the Gibbs probability distribution corresponding to the conditions of network preparation. To our mind, it is a beautiful idea but it should be considered more deeply because not all the types of networks can be described in such a way - many networks cannot be prepared under any equilibrium conditions. Using some additional tube-like approximations, the authors have obtained rather simple results for network elastic constants and for some other parameters. 

Blondel, A. Ensemble variance in free energy calculations by thermodynamic integration theory, optimal alchemical path, and practical solutions, J. Comp. Chem. 2004, 25(7), 985-93. 

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