Question

When performing molecular docking, why must a scoring function include a term to calculate the energetic penalty for overlapping atomic van der Waals radii?

Accepted Answer

In molecular docking, the scoring function estimates the binding affinity between a ligand and a target protein by calculating the total energy of their interaction. A critical component of this function is the penalty for overlapping atomic van der Waals radii, which accounts for the physical reality that two atoms cannot occupy the same space. The van der Waals radius represents the effective size of an atom, defined as the distance of closest approach for another non-bonded atom. If atoms are placed closer than the sum of their van der Waals radii, they experience a massive repulsive force known as Pauli repulsion. This occurs because the electron clouds of the atoms begin to overlap, causing the negatively charged electrons to strongly repel each other. Without an energetic penalty term to penalize these spatial overlaps, a scoring function would incorrectly identify geometrically impossible protein-ligand conformations as highly stable or favorable. For example, if a carbon atom from a drug molecule were allowed to occupy the same position as a carbon atom in a protein binding site without a penalty, the scoring function would fail to recognize the physical impossibility of the arrangement. By imposing a severe energetic cost for atomic clashes, the scoring function ensures that only physically realistic, non-overlapping poses are considered potential binding candidates.

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When performing molecular docking, why must a scoring function include a term to calculate the energetic penalty for overlapping atomic van der Waals radii?