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The Uniform Power of Potential: How FEP Became the Secret Weapon in Drug Discovery?
In the drug discovery process, one of the challenges researchers face is how to accurately calculate the difference in free energy between different molecules. This work is critical to the development of new drugs because the stability and activity of many molecules directly affect their medical effectiveness. Since the free energy perturbation (FEP) method was introduced by Robert W. Zwanzig in 1954, this technique has become an important tool in the field of computational chemistry.
The free energy perturbation method is based on statistical mechanics and calculates the free energy difference from state A to state B through molecular dynamics or Monte Carlo simulation. According to the FEP method, the obtained free energy difference is given by the following formula:
ΔF(A → B) = FB - FA = -kBT ln ⟨exp(- (EB - EA)/kBT) A
Among them, T is the temperature, kB is Boltzmann's constant, and the angle brackets indicate the average of the simulation running results of state A. In practical applications, researchers usually run regular simulations for state A, and each time a new configuration is accepted, the energy of state B is also calculated. The difference between state A and state B can be a change in the type of atoms involved, or a change in structural geometry, so that the calculated ΔF is "changing one molecule into another" or is based on one or more A free energy map of a reaction coordinate, also known as the mean force potential (PMF).
However, free energy perturbation calculations will only converge correctly if the gap between the two states is small enough. Therefore, the perturbation usually needs to be divided into a series of smaller "windows", which need to be calculated independently. Since the simulation between each window does not require continuous communication, the process can be easily parallelized, a so-called "shameless parallel" setup.
Application of FEP
Free energy perturbation calculations have applications in many fields, including studying the energetics of host-guest binding, pKa prediction, studying the effects of solvents on reactions, and enzymatic reactions. Especially in drug discovery, this technology is used for virtual screening of ligands, computational mutation, and antibody affinity maturation. In order to study certain reactions, it is often necessary to involve quantum mechanical representations, because the force fields of molecular mechanics cannot handle the situation of broken bonds. Therefore, hybrid methods that combine the advantages of quantum mechanics and molecular mechanics are applied to these calculations.
"FEP fully demonstrates the potential of computational materials science and drug design processes."
Another common free energy calculation technique is umbrella sampling, which is mainly used to calculate the free energy changes accompanying changes in position coordinates, although this method can also be used to study chemical transformations. In addition, the thermodynamic integration method is an alternative to FEP in calculating the mean force potential, while the Bennett acceptance ratio method is considered to be more efficient. With the development of these technologies, the adaptability and application scope of FEP continue to expand, such as the allocation calculation of free energy changes in sub-regions of chemical structures.
FEP related software
In order to facilitate scientific researchers to perform FEP calculations, a variety of professional software has been launched on the market, including:
- Flare
- FEP
- FEP+
- AMBER
- BOSS
- CHARMM
- Desmond
- GROMACS
- MacroModel
- MOLARIS
- NAMD
- Tinker
- Q
- QUELO
Conclusion
Overall, free energy perturbation methods have undoubtedly become an indispensable tool in the fields of drug discovery and materials science. By accurately calculating the interactions between molecules, FEP can not only accelerate the drug development process, but also improve our understanding of cellular and molecular mechanisms. However, with the development of new technologies and theoretical advancement, what challenges and opportunities will free energy perturbation methods still face in the future?
