Comparing the force-field performance in water with the values for the same compound in chloroform, we find contrasting results for roxithromycin and telithromycin. To rationalize these results, we performed a clustering of each trajectory (as described in the Methods section) to extract five clusters, and compare between the representative structures. The most populated conformations (cluster 0) of roxithromycin in water and chloroform are very similar. However, while this structure agrees well with the experimental data in chloroform (Figure ), the NOE upper bounds indicate that there should be additional contacts in water (Figure ).