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Membrane Proteins Have Distinct Fast Internal Motion and Residual Conformational Entropy.

ABSTRACT: The internal motions of integral membrane proteins have largely eluded comprehensive experimental characterization. Here the fast side-chain dynamics of the ?-helical sensory rhodopsin?II and the ?-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.

SUBMITTER: O'Brien ES

PROVIDER: S-EPMC7318686 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Membrane Proteins Have Distinct Fast Internal Motion and Residual Conformational Entropy.

O'Brien Evan S ES Fuglestad Brian B Lessen Henry J HJ Stetz Matthew A MA Lin Danny W DW Marques Bryan S BS Gupta Kushol K Fleming Karen G KG Wand A Joshua AJ

Angewandte Chemie (International ed. in English) 20200430 27

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 ...[more]

PMID: 32277554

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Project description:NMR spin relaxation retains a central role in the characterization of the fast internal motion of proteins and their complexes. Knowledge of the distribution and amplitude of the motion of amino acid side chains is critical for the interpretation of the dynamical proxy for the residual conformational entropy of proteins, which can potentially significantly contribute to the entropy of protein function. A popular treatment of NMR relaxation phenomena in macromolecules dissolved in liquids is the so-called model-free approach of Lipari and Szabo. The robustness of the mode-free approach has recently been strongly criticized and the remarkable range and structural context of the internal motion of proteins, characterized by such NMR relaxation techniques, attributed to artifacts arising from the model-free treatment, particularly with respect to the symmetry of the underlying motion. We develop an objective quantification of both spatial and temporal asymmetry of motion and re-examine the foundation of the model-free treatment. Concerns regarding the robustness of the model-free approach to asymmetric motion appear to be generally unwarranted. The generalized order parameter is robustly recovered. The sensitivity of the model-free treatment to asymmetric motion is restricted to the effective correlation time, which is by definition a normalized quantity and not a true time constant and therefore of much less interest in this context. With renewed confidence in the model-free approach, we then examine the microscopic distribution of side chain motion in the complex between calcium-saturated calmodulin and the calmodulin-binding domain of the endothelial nitric oxide synthase. Deuterium relaxation is used to characterize the motion of methyl groups in the complex. A remarkable range of Lipari-Szabo model-free generalized order parameters are seen with little correlation with basic structural parameters such as the depth of burial. These results are contrasted with the homologous complex with the neuronal nitric oxide synthase calmodulin-binding domain, which has distinctly different thermodynamic origins for high affinity binding.

Dataset Information

Membrane Proteins Have Distinct Fast Internal Motion and Residual Conformational Entropy.

Publications

Membrane Proteins Have Distinct Fast Internal Motion and Residual Conformational Entropy.

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