20,014 research outputs found
Extending fragment-based free energy calculations with library Monte Carlo simulation: Annealing in interaction space
Pre-calculated libraries of molecular fragment configurations have previously
been used as a basis for both equilibrium sampling (via "library-based Monte
Carlo") and for obtaining absolute free energies using a polymer-growth
formalism. Here, we combine the two approaches to extend the size of systems
for which free energies can be calculated. We study a series 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
Simultaneous computation of dynamical and equilibrium information using a weighted ensemble of trajectories
Equilibrium formally can be represented as an ensemble of uncoupled systems
undergoing unbiased dynamics in which detailed balance is maintained. Many
non-equilibrium processes can be described by suitable subsets of the
equilibrium ensemble. Here, we employ the "weighted ensemble" (WE) simulation
protocol [Huber and Kim, Biophys. J., 1996] to generate equilibrium trajectory
ensembles and extract non-equilibrium subsets for computing kinetic quantities.
States do not need to be chosen in advance. The procedure formally allows
estimation of kinetic rates between arbitrary states chosen after the
simulation, along with their equilibrium populations. We also describe a
related history-dependent matrix procedure for estimating equilibrium and
non-equilibrium observables when phase space has been divided into arbitrary
non-Markovian regions, whether in WE or ordinary simulation. In this
proof-of-principle study, these methods are successfully applied and validated
on two molecular systems: explicitly solvated methane association and the
implicitly solvated Ala4 peptide. We comment on challenges remaining in WE
calculations
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