dealt with in the subsequent Sect. 2.3.2. However, measuring the dissociation
constants from simulations is a daunting task; nevertheless, computing the partition
functions from the molecular simulations is relatively easy. Hence, the ratios of the
partition functions can be used to estimate the free energy of binding, which is
given by Eq. 2a,
DG ¼ Àk B T ln
Q PL
Q P Q L
ð2aÞ
where k B is the Boltzmann constant, T is the temperature in Kelvin, Q is the
partition function with subscripts PL, P and L indicating protein–ligand complex,
protein, and ligand, respectively. This section presents a summary of thermodynamics, which is imperative for understanding the application and methods
developed to compute binding free energy. More elaborate discussions on the
thermodynamics of protein–ligand binding can be found in the reviews by
Bronowska [48], and Homans [46].
2.3 Methods to Compute Free Energy Binding
Free energy is a quantity that can be measured for systems such as liquids or
flexible macromolecules with several minimum energy configurations separated by
high-energy barriers. However, its computation is far from trivial and the associated
quantities such as entropy and chemical potential are also difficult to calculate.
More so, the free energy cannot be accurately determined from classical molecular
Fig. 1 Thermodynamic or Born–Haber cycle for the receptor-ligand binding
Free Energy-Based Methods to Understand Drug Resistance Mutations
7
constants from simulations is a daunting task; nevertheless, computing the partition
functions from the molecular simulations is relatively easy. Hence, the ratios of the
partition functions can be used to estimate the free energy of binding, which is
given by Eq. 2a,
DG ¼ Àk B T ln
Q PL
Q P Q L
ð2aÞ
where k B is the Boltzmann constant, T is the temperature in Kelvin, Q is the
partition function with subscripts PL, P and L indicating protein–ligand complex,
protein, and ligand, respectively. This section presents a summary of thermodynamics, which is imperative for understanding the application and methods
developed to compute binding free energy. More elaborate discussions on the
thermodynamics of protein–ligand binding can be found in the reviews by
Bronowska [48], and Homans [46].
2.3 Methods to Compute Free Energy Binding
Free energy is a quantity that can be measured for systems such as liquids or
flexible macromolecules with several minimum energy configurations separated by
high-energy barriers. However, its computation is far from trivial and the associated
quantities such as entropy and chemical potential are also difficult to calculate.
More so, the free energy cannot be accurately determined from classical molecular
Fig. 1 Thermodynamic or Born–Haber cycle for the receptor-ligand binding
Free Energy-Based Methods to Understand Drug Resistance Mutations
7