Free energy perturbation calculations on parallel computers: Demonstrations of scalable linear speedup

A coarse‐grain parallel implementation of the free energy perturbation (FEP) module of the AMBER molecular dynamics program is described and then demonstrated using five different molecular systems. The difference in the free energy of (aqueous) solvation is calculated for two monovalent cations ΔΔ G aq (Li + Δ Cs + ), and for the zero‐sum ethane‐to‐ethane′ perturbation ΔΔ G aq (CH 3 methyl X → X methylCH 3 ), where X is a ghost methyl. The difference in binding free energy for a docked HIV‐1 protease inhibitor into its ethylene mimetic is examined by mutating its fifth peptide bond, Δ G (CONH → CHCH). A potassium ion (K + ) is driven outward from the center of mass of ionophore salinomycin (SAL − ) in a potential of mean force calculation Δ G MeOH (SAL − · K + ) carried out in methanol solvent. Parallel speedup obtained is linearly proportional to the number of parallel processors applied. Finally, the difference in free energy of solvation of phenol versus benzene, ΔΔ G oct (phenol → benzene), is determined in water‐saturated octanol and then expressed in terms of relative partition coefficients, Δ log( P o/w ). Because no interprocessor communication is required, this approach is scalable and applicable in general for any parallel architecture or network of machines. FEP calculations run on the nCUBE/2 using 50 or 100 parallel processors were completed in clock times equivalent to or twice as fast as a Cray Y‐MP. The difficulty of ensuring adequate system equilibrium when agradual configurational reorientation follows the mutation of the Hamiltonian is discussed and analyzed. The results of a successful protocol for overcoming this equilibration problem are presented. The types of molecular perturbations for which this method is expected to perform most efficiently are described. © 1994 by John Wiley & Sons, Inc.