Dense packing of a protein's interior, depicted in (a), suggests that few side-chain arrangements are sterically consistent with a particular backbone conformation. Results of Monte Carlo simulations, plotted in (b), demonstrate that this inference is wildly incorrect. Roughly 10⁴⁶ distinct rotameric states satisfy steric constraints, the vast majority of which differ appreciably from the crystallographically determined structure. Neglecting energetics of side-chain interactions, this observation (first made by Shakhnovich and coworkers) indicates substantial equilibrium fluctuations in side-chain rotations. Professor Geissler and graduate student Kateri DuBay are working to characterize spatial correlations among these motions. Detailed calculations, such as those depicted in (c) for photoactive yellow protein, confirm that constraining rotations of a single side-chain, even on the molecule's exterior, can bias rotamer statistics of distant residues. Changes in residue mobility upon ligand binding could thus extend over large distances for steric reasons alone. This effect might help to explain unexpected patterns of ligand induced mobility changes (d) inferred from recent NMR measurements.