Siebenmorgen2020Computational_w8

[cramg]

Siebenmorgen, Till, and Martin Zacharias. “Computational Prediction of Protein–Protein Binding Affinities.” Wiley Interdisciplinary Reviews: Computational Molecular Science 10, no. 3 (2020).

[cramg]

The authors highlight the need of study all possible protein-protein interactions in order to understanding cellular processes. They pointed out the importance of the complex's geometry and their degrees of freedom at the time of calculating binding free energy with the methods exposed. Something that caught my attention were the limitations of MM/PBSA and MM/GBSA calculations and the desire of an approach that consider an explicit solvent representation along with the other approximations in order to obtain better binding free energies and affinities calculations.

[cramg]

Question:

-What's the difference between calculate binding free energies and protein-protein affinity?

[dprada]

@cramg That's a very good question. It's basically the same. The two sides of the same coin.

When two molecules interact up to the point of binding (making a complex), the binding free energy is the free energy difference between the bound state and the unbound state of the system. You can think that this magnitude is the work you need to bring the two molecules from their isolated states (an infinite distance apart) to the bound state -or the opposite, breaking the complex-. Actually, the binding free energy that we now denote with $\Delta F$, originally was written as $\Delta A$, where A stands for the word 'arbeit' ('work' in German).

The binding affinity is the strength of the binding interaction between these two molecules and it is typically measured and reported by the equilibrium dissociation constant (KD), or the equilibrium association constant (KA = 1/KD). The smaller the KD value, the greater the binding affinity of the ligand for its target. The larger the KD value, the more weakly the target molecule and ligand are attracted to and bind to one another.

But, we know that there is a straight relationship between the binding free energy and KD (or KA). Let's take the reaction "on"<-->"off" in equilibrium, the probability (or concentration) of having the system in "on", and the probability of "off" can be calculated from the free energy of each state:

Pon = (1/Z) * exp (- \beta Fon)
Poff = (1/Z) * exp (- \beta Foff)
Z = exp (- \beta Fon) + exp (- \beta Foff)

And the definition of KD is:

KD = Poff / Pon

Or in terms of the free energies:

KD = Poff / Pon = exp[-\beta (Foff-Fon)] = exp(-\beta \Delta F)

As you see, both concepts are the two sides of the same coin. And the coin represents how much you pay to put two molecules together...

[cramg]

Thanks a lot!