EXTRACTING EQUILIBRIUM UNBINDING FREE ENERGY OF PROTEIN-DRUG COMPLEXES FROM NONEQUILIBRIUM SIMULATIONS

The use of protein-ligand binding free-energy landscapes rationalizes a wide range of aspects of protein behaviour in response to the ligand approach by providing a clear illustration of the different states accessible to these molecules, as well as of their populations and interaction pathways. To achieve this goal by computational methods is, however, very challenging as it requires an extensive sampling of their conformational spaces. Additionally, at an equilibrium condition, (un)binding events of ligands happen on the milliseconds or longer time scale, and is therefore not amenable to study through conventional MD (CMD) simulation techniques. Various nonequilibrium simulation protocols have been articulated to overcome this challenge with their associated utility and pitfalls. Here we will focus on two such protocols, namely, the steered molecular dynamics (SMD) and the popular metadynamics (MtD) method in relation to unbinding free energy of acetylcholinesterase (AChE) bound oxime drugs along the gorge pathway. Unfortunately however, both these methods suffer from inherent nonequilibrium features. To circumvent this we arrive at a simulation recipe, combining the strengths of equilibrium and nonequilibrium simulation techniques, that can readily decipher routes, milestones and subtlety towards the (un)binding pathway of ligand at finite temperature. Dr. Tusar Bandyopadhyay is the recipient of the DAE Scientific & Technical Excellence Award for the year 2012