Well-Tempered Variational Approach to Enhanced Sampling.

We propose a simple yet effective iterative scheme that allows us to employ the well-tempered distribution as a target distribution for the collective variables in our recently introduced variational approach to enhanced sampling and free energy calculations [ Valsson and Parrinello Phys. Rev. Lett. 2014 , 113 , 090601 ]. The performance of the scheme is evaluated for the three-dimensional free energy surface of alanine tetrapeptide where the convergence can be rather poor when employing the uniform target distribution. Using the well-tempered target distribution on the other hand results in a significant improvement in convergence. The results observed in this paper indicate that the well-tempered distribution is in most cases the preferred and recommended choice for the target distribution in the variational approach.