CDH23 structure showing the pathogenic DVD variant Val 1090 Ile. (a) The wild-type CDH23 model for residues 887–1408 is shown, with Val 1090 highlighted by a red box. (b) Shown in spacefill format are Val 1039 and Val 1090. (c) After AMOEBA/GK repacking, the conformation of Val 1039 changes relative to the variant. (d) A clash is present between Val 1039 and the Ile 1090 variant, which is consistent with altered folding stability and classification as disease causing. This example illustrates that without repacking, downstream free-energy simulation timescales must (in general) increase to allow relaxation of nonoptimal side-chain conformations. To see this figure in color, go online.