Abstract

A two part presentation demonstrates the use of computational methods in deciphering reaction mechanisms of protein-ligand interactions, i.e. mechanisms of inhibition and stimulation. The first part presents an example of a ligand as inhibitor. A statistical mechanical framework based on Inhomogeneous Fluid Solvation Theory is used to determine underlying mechanism of potency of an inhibitor toward a protein. Since all drugs acting on proteins are inhibitors the example shows a method to asses protein’s druggability. The second part presents an example of a ligand as agonist. A mechanism of nerve signal transduction via GPC Rs is proposed. It is based on idea that a neurotransmitter interacts with not only residues of a protein but with its helical backbone structure. This interaction triggers a conformational change between 3-10 and 4-13 forms of the helix, in other words helix springs. At the end we can discussion about fundamentally opposing modes of mechanisms between ligands (inhibitors and agonists), as well as between proteins (enzymes and receptors, where enzymes change the ligand while receptors change itself).