We finally compare conformational sampling using standard HREM, HREM with acceptance ratio balancing (Eq. 4) and MD replicates for the simulation of the BRD4(I) in complex with the ligand ODR (see Figure ). Technical details of the simulation are provided in Sec. 3.2. In Figure In Table , we have collected all relevant parameters for the HREM simulation of the ORD-BRD4(I) complex in explicit solvent. The sub-system, involved in 12-fold scaling down to s min = 0.1, includes the ligand and the hot-zone residues for a total of 183 atoms, comparable to the number of atoms in compound 2 (157), which was simulated using the same HREM protocol. As a trivial consequence of this fact, we observe the same pattern in the acceptance ratio using the standard scaling Eq. 3 in the the BRD4(I) complex and in compound 2 with P acc (k) steadily and 28% for compound 2). As observed for the HREM simulations of compound 2, also in the case of the BRD4(I)-ODR complex, the flux and RTT are slightly improved by implementing the acceptance ratio balancing via Eq. 4. In the BRD4(I)-ODR complex we observe only a moderate degradation of the mean acceptance ratio upon ten iteration cycles (lasting 1.6 ns in total) of implementing Eq. 4, at variance with what was observed in compounds 1 and 2 (see Tables and). As in compound 1 and 2, the variance S (Eq. 6) increases when using Eq. 4. In Figure Å (see Figure ) is sampled five and and seven times in the standard and the adaptive HREM simulation, respectively, with a probability around 7% in both cases.