Challenges Encountered Applying Equilibrium and Nonequilibrium Binding Free Energy Calculations

Near-equilibrium measurements of nonequilibrium free energy.

A central endeavor of thermodynamics is the measurement of free energy changes. Regrettably, although we can measure the free energy of a system in thermodynamic equilibrium, typically all we can say about the free energy of a nonequilibrium ensemble is that it is larger than that of the same system at equilibrium. Herein, we derive a formally exact expression for the probability distribution o...

Equilibrium and nonequilibrium foundations of free energy computational methods

Statistical mechanics provides a rigorous framework for the numerical estimation of free energy di erences in complex systems such as biomolecules. This paper presents a brief review of the statistical mechanical identities underlying a number of techniques for computing free energy di erences. Both equilibrium and nonequilibrium methods are covered.

Free energy calculations and ligand binding.

Path-breaking schemes for nonequilibrium free energy calculations.

We propose a path-breaking route to the enhancement of unidirectional nonequilibrium simulations for the calculation of free energy differences via Jarzynski's equality [C. Jarzynski, Phys. Rev. Lett. 78, 2690 (1997)]. One of the most important limitations of unidirectional nonequilibrium simulations is the amount of realizations necessary to reach suitable convergence of the work exponential a...

Conformational Transitions and Convergence of Absolute Binding Free Energy Calculations.

The Binding Energy Distribution Analysis Method (BEDAM) is employed to compute the standard binding free energies of a series of ligands to a FK506 binding protein (FKBP12) with implicit solvation. Binding free energy estimates are in reasonably good agreement with experimental affinities. The conformations of the complexes identified by the simulations are in good agreement with crystallograph...