Among the energy functions, no single Biphenyl-indanone A function consistently outperformed the others for all targets in detecting conformers with the highest fN. Nevertheless, for both the CKI-7 dihydrochloride adaptive and static T-ReX simulations, RWplus yielded the highest average fN of roughly 0.63, while the lowest is given by CHARMM22/GBMV2 with a value of 0.60. The average maximum fN sampled from the simulations of all targets is 0.74 for the adaptive T-ReX and 0.72 for the static method. While these sampling excursions seem to approach the downhill refinement regime on the force-field potential energy landscape for both methods, the conformational populations of these basins and their detection from the energy functions were disappointedly poor. Using the alternative RMSD metric to assess refinement, the overall trend from the energy functions is similar to that of fN. The RWplus yielded the lowest-average Ca RMSD decoy detection of 2.6 A �� for the adaptive T-ReX sampling and 2.2 A �� for the static method. The lowest-RMSD values sampled overall from the simulations were 1.7 A �� using the adaptive method and 1.6 A �� for the static method. The starting decoy set of 16 conformers per target exhibited a net average Ca RMSD of 3.5 A ��, with values ranging from 1.4 A �� to 10.7 A ��. Collectively, the static method achieved lower RMSD values for the combined energy functions and, as illustrated below, this is related to the dynamics of heating and cooling clients by the adaptive method driven by the topology of the CHARMM22/GBMV2 energy landscape. To better understand the effects of temperature exchanges on conformational excursions, Fig. 2 shows a comparison between the adaptive and static T-ReX simulations in sampling Ca-RMSD space as a function of client temperature. Since the adaptive method dynamically walks in temperature space, we selected to apply the final converged temperature set as an approximate of histograms over the evolved temperature path. The comparison of the two T-ReX methods shows in general the adaptive method produces a lower average Ca-RMSD exploration and thus indicates less diverse sampling. Overall statistical fluctuations in the averages between the two methods are comparable. Difference in excurions result follows from the diffusive flow of clients between the two temperature extremes and the enrichment of client populations near energetic barriers.