Do ultrastable proteins from hyperthermophiles have high or low conformational rigidity?

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Abstract
Life on earth has an unbelievable adaptive capacity. Except for centers of volcanic activity, the entire surface of our planet is a biosphere. In this context, the most surprising discovery in our lifetime was the expansion from the anthropocentrically defined “normal temperature” of mesophiles (<40°C) to the optimum temperature range of hyperthermophiles around and above the boiling point of water. That in this class of microorganisms high temperature is required for growth rather than tolerated implies that the whole repertoire of their biomolecules must be sufficiently stable to allow the cellular microcosm to work. The strategies nature has used to stabilize the inventory of the cell, especially proteins, under extreme conditions are still enigmatic, despite 25 years of active research. What has become clear is that proteins, independent of their mesophilic or extremophilic origin, consist exclusively of the canonical 20 natural amino acids; if other protein constituents are found, they originate from covalent chemical modifications (1). Thus, enhanced stability can come from only improved attractive forces: within the core, between domains and subunits, or from extrinsic protectants such as compatible solutes, conjugating components, and specific metabolites. The second alternative has been explained in terms of preferential solvation or specific ligand binding (2). For the first, a variety of “rules” has been proposed without providing an unambiguous solution to the problem. The reason for this failure is simple: considering the thermodynamic characteristics of proteins from mesophiles and extremophiles, the free energies of stabilization differ only marginally. The adaptive changes in terms of free energy differences (ΔΔ G stab) correspond to the equivalent of just a few weak intermolecular interactions (3). Given the large number of small increments from hydrogen bonds, as well as hydrophobic, coulombic, and van der Walls interactions in molecules with hundreds or even thousands of atoms, there may …