Before revision: We have combined and integrated our previously developed library-based Growth and Monte Carlo simulation techniques in order to allow for both thorough sampling and free energy measurements of all-atom peptides. The integrated growth and relaxation technique makes use of pre-calculated Boltzmann distributed statistical libraries of molecular-fragments and their corresponding energies . Due to this new implementation, we are now able to accurately determine free energies and sample phase space for larger systems that were previously unattainable with library-based growth. We report sampling quality and statistics on free energy measurements for four polypeptide systems that we examined. We discuss possible applications of this new and more general library-based method .
After revision: We have combined and integrated our previously developed library-based Growth and Monte Carlo simulation techniques in order to allow for both thorough sampling and free energy measurements of all-atom poly-alanine systems in a simple dielectric "solvent" and find that precise free energies can be obtained rapidly. For instance, for 12 residues, less than an hour of single-processor is required. The combined approach is formally equivalent to the "annealed importance sampling" algorithm; instead of annealing by decreasing temperature, however, interactions among fragments are gradually added as the molecule is "grown." We discuss implications for future binding affinity calculations in which a ligand is grown into a binding site .