(local elevation method [38] Metadynamics [39]) uses Gaussian potentials that
discourage the system from sampling the same conformational space. These are few
of the most commonly used methods to tackle sampling problems in molecular
dynamics, a complete account on enhanced sampling algorithms can be found
elsewhere [40–44].
2.2 An Overview of Thermodynamics of Protein–Ligand
Binding
Molecular interactions, between the ligand and receptor, are primarily non-covalent
in nature and governed by attractive and repulsive forces. In drug design experiments, the goal is always to optimize the attractive interactions and reduce the
repulsive ones [45–47]. Moreover, these associations are temporary, and the
lifespan of such complexes are governed by the off rates (K off ) or the dissociation
constant (K d ), both of which indicate the binding strength of a ligand to its protein
counterpart. In the realm of thermodynamics, binding is governed by enthalpic and
entropic components [48] given by Eq. 1.
DG ¼ DH À TDS
ð1Þ
where ΔG is the binding free energy; ΔH is enthalpy; ΔS is entropy and T is the
temperature in Kelvin.
The association is favourable, i.e. spontaneous when the ΔG Gibbs is negative and
unfavourable otherwise. All the binding and pre-binding (recognition and
pre-organization) events in biomolecular associations are either enthalpy
(ΔH) driven or entropy (ΔS) driven. The enthalpic component represents several
types of non-covalent interactions like electrostatic, van der Waals, ionic, hydrogen
bonds and halogen bonds, while the entropic components reflect the contribution to
binding due the dynamics or flexibility of the system. Computing the enthalpic
component of binding has reached far heights, in terms of methods available for
calculating the aforementioned type of interactions. However, till date, calculation
of the entropic component is extremely difficult, and the algorithms are computationally very demanding.
The Gibbs equation is more relevant in biochemistry for calculating the free
energy and is given by Eq. 2:
DG Gibbs ¼ ÀRT ln K d
ð2Þ
where ΔG Gibbs is Gibbs free energy, R is universal gas constant, T is the temperature
in Kelvin, K d is the dissociation constant. Equations 1 and 2, along with the
Born–Haber cycle [46] (Fig. 1) form the basis for the development of the methods
used to compute the free energy binding. The two main methods are Free energy
perturbation (FEP) and Thermodynamics Integration (TI), both of which will be
6
E. A. F. Martis and E. C. Coutinho
discourage the system from sampling the same conformational space. These are few
of the most commonly used methods to tackle sampling problems in molecular
dynamics, a complete account on enhanced sampling algorithms can be found
elsewhere [40–44].
2.2 An Overview of Thermodynamics of Protein–Ligand
Binding
Molecular interactions, between the ligand and receptor, are primarily non-covalent
in nature and governed by attractive and repulsive forces. In drug design experiments, the goal is always to optimize the attractive interactions and reduce the
repulsive ones [45–47]. Moreover, these associations are temporary, and the
lifespan of such complexes are governed by the off rates (K off ) or the dissociation
constant (K d ), both of which indicate the binding strength of a ligand to its protein
counterpart. In the realm of thermodynamics, binding is governed by enthalpic and
entropic components [48] given by Eq. 1.
DG ¼ DH À TDS
ð1Þ
where ΔG is the binding free energy; ΔH is enthalpy; ΔS is entropy and T is the
temperature in Kelvin.
The association is favourable, i.e. spontaneous when the ΔG Gibbs is negative and
unfavourable otherwise. All the binding and pre-binding (recognition and
pre-organization) events in biomolecular associations are either enthalpy
(ΔH) driven or entropy (ΔS) driven. The enthalpic component represents several
types of non-covalent interactions like electrostatic, van der Waals, ionic, hydrogen
bonds and halogen bonds, while the entropic components reflect the contribution to
binding due the dynamics or flexibility of the system. Computing the enthalpic
component of binding has reached far heights, in terms of methods available for
calculating the aforementioned type of interactions. However, till date, calculation
of the entropic component is extremely difficult, and the algorithms are computationally very demanding.
The Gibbs equation is more relevant in biochemistry for calculating the free
energy and is given by Eq. 2:
DG Gibbs ¼ ÀRT ln K d
ð2Þ
where ΔG Gibbs is Gibbs free energy, R is universal gas constant, T is the temperature
in Kelvin, K d is the dissociation constant. Equations 1 and 2, along with the
Born–Haber cycle [46] (Fig. 1) form the basis for the development of the methods
used to compute the free energy binding. The two main methods are Free energy
perturbation (FEP) and Thermodynamics Integration (TI), both of which will be
6
E. A. F. Martis and E. C. Coutinho