Equation 15 is usually referred to as the thermodynamic integration (TI) method
for calculating the free energy change [86, 87]. In the early days of free energy
simulations, the TI approach was synonymous with the slow-growth method [88].
In the slow-growth method, the value of k is changed at each time step during the
MD simulation. While this method was claimed to be more efficient than the
discrete FEP formulation, nowadays, a “non-continuous” change in k is a better
choice (50–100 discrete points are usually recommended). This facilitates equilibration at each point, the addition of extra points at any time, and use of any pattern
of spacing between the k-points, to optimize the efficiency.
Alchemical Free Energy Perturbation
Here, the free energy is computed by transforming a molecule from one state
(bound-solvated) to another state (unbound-solvated) through several physically
unrealistic states, that are called as alchemical states, hence the name “Alchemical
Free energy” [89, 90]. This method is regarded as one of the apt methods to study
Fig. 2 Thermodynamics cycle for computing alchemical free energy binding. Image reproduced
from Wang et al. [91] [open-access article distributed under the terms of the Creative Commons
Attribution License (CC BY)]
Free Energy-Based Methods to Understand Drug Resistance Mutations
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