Extending fragment-based free energy calculations with library Monte Carlo simulation: Annealing in interaction space

TL;DR

This paper introduces a novel method combining library-based Monte Carlo with annealing in interaction space to efficiently compute free energies of larger molecular systems, enabling rapid and precise calculations.

Contribution

It extends fragment-based free energy calculations by integrating library Monte Carlo with an annealing approach in interaction space, allowing larger system analysis.

Findings

Precise free energies obtained rapidly for 12-residue systems

Method is equivalent to annealed importance sampling but with interaction-based annealing

Potential applications in ligand binding affinity calculations

Abstract

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.