The use of fast free energy methods in rational drug design

Abstract

The computationally demanding nature and lack of generality of free energy methods are the main barriers to their common place use in rational drug design.  This study investigates the possibility of producing protocols to accurately calculate the binding free energy of protein-ligand complexes more efficiently than presently established methods, using large scale distributed computing.  There has been an explosion of useful nonequilibrium work methods recently, mainly due to the discovery of the Jarzynski equilibrium.  After an in depth investigation of these methods, a subset, all with the possibility of large scale parallelisation, was chosen for further study.  Also, replica exchange fast-growth (REFG), was developed, a method which combines replica exchange and fast growth methods in a similar way to replica exchange thermodynamic integration (RETI).  These methods of interest were applied to a large number of harmonic oscillator systems and compared to the established method TI.  Those methods deemed to perform best were then applied to some simple solute-solvent test systems and compared to the established method RETI.  The best performing method from these studies was then compared to RETI for the calculation of relative binding free energies of two sets of cogeneric inhibitors bound to their receptor proteins.  REFG was found to perform as well as RETI and produce constantly predictive results.  REFG was able to produce these results in significantly less wall clock time by using large scale distributed computing.

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