Exploring the free-energy landscape of a short peptide using an average force

The reversible folding of deca-alanine is chosen as a test case for characterizing a method that uses an adaptive biasing force (ABF) to escape from the minima and overcome the barriers of the free-energy landscape. This approach relies on the continuous estimation of a biasing force that yields a Hamiltonian in which no average force is exerted along the ordering parameter $ξ$⁠. Optimizing the parameters that control how the ABF is applied, the method is shown to be extremely effective when a nonequivocal ordering parameter can be defined to explore the folding pathway of the peptide. Starting from a $β$-turn motif and restraining $ξ$ to a region of the conformational space that extends from the $α$-helical state to an ensemble of extended structures, the ABF scheme is successful in folding the peptide chain into a compact $α$ helix. Sampling of this conformation is, however, marginal when the range of $ξ$ values embraces arrangements of greater compactness, hence demonstrating the inherent limitations of free-energy methods when ambiguous ordering parameters are utilized.