The relationship between the NMR methyl group axial order parameter and the side chain conformational entropy is investigated in inhibitor-bound and apo human HIV protease using molecular dynamics simulation. Three distinct entropic classes of methyl-bearing side chains, determined by the topological distance of the methyl group from the protein backbone (i.e., the number of chi-bonds between the C-alpha and the carbon of the CH3 group), are revealed by atomistic trajectory analyses performed in the local frame of reference of individual methyl probes. The results demonstrate that topologically equivalent methyl groups experience similar nonbonded microenvironments regardless of the type of residues to which they are attached. Similarly, methyl groups that belong to the same side chain but that are not topologically equivalent exhibit different thermodynamic and dynamic properties. The two-parameter classification (based upon entropy and methyl axial order parameter) of side chains described here permits improved estimates of the conformational entropies of proteins from NMR motional parameters.