Membrane Proteins Have Distinct Fast Internal Motion and Residual Conformational Entropy

The internal motions of integral membrane proteins have largely eluded comprehensive experimental characterization. Here the fast side‐chain dynamics of the α‐helical sensory rhodopsin II and the β‐barrel outer membrane protein W have been investigated in lipid bilayers and detergent micelles by solution NMR relaxation techniques. Despite their differing topologies, both proteins have a similar distribution of methyl‐bearing side‐chain motion that is largely independent of membrane mimetic. The methyl‐bearing side chains of both proteins are, on average, more dynamic in the ps–ns timescale than any soluble protein characterized to date. Accordingly, both proteins retain an extraordinary residual conformational entropy in the folded state, which provides a counterbalance to the absence of the hydrophobic effect. Furthermore, the high conformational entropy could greatly influence the thermodynamics underlying membrane‐protein functions, including ligand binding, allostery, and signaling. Two membrane proteins (one α‐helical and one β‐barrel) have been found, using solution NMR relaxation techniques, to have extraordinary side‐chain motion on the ps–ns timescale in both detergent micelles and lipid bilayers. The extensive side‐chain motion about a highly rigid backbone scaffold is consistent with a high residual conformational entropy and helps explain the stability of the folded state in the absence of the hydrophobic effect.