title: Rigidity versus flexibility: the dilemma of understanding protein thermal stability.
abstract: The role of fluctuations in protein thermostability has recently received considerable attention. In the current literature a dualistic picture can be found: thermostability seems to be associated with enhanced rigidity of the protein scaffold in parallel with the reduction of flexible parts of the structure. In contradiction to such arguments it has been shown by experimental studies and computer simulation that thermal tolerance of a protein is not necessarily correlated with the suppression of internal fluctuations and mobility. Both concepts, rigidity and flexibility, are derived from mechanical engineering and represent temporally insensitive features describing static properties, neglecting that relative motion at certain time scales is possible in structurally stable regions of a protein. This suggests that a strict separation of rigid and flexible parts of a protein molecule does not describe the reality correctly. In this work the concepts of mobility/flexibility versus rigidity will be critically reconsidered by taking into account molecular dynamics calculations of heat capacity and conformational entropy, salt bridge networks, electrostatic interactions in folded and unfolded states, and the emerging picture of protein thermostability in view of recently developed network theories. Last, but not least, the influence of high temperature on the active site and activity of enzymes will be considered.
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Andrey
authors.initials: A
authors.lastname: Karshikoff
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Lennart
authors.initials: L
authors.lastname: Nilsson
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Ladenstein
mesh_terms: D000818:Animals; D055162:Biocatalysis; D020134:Catalytic Domain; D003080:Cold Temperature / Q000009:adverse effects; D019277:Entropy; D004795:Enzyme Stability; D006358:Hot Temperature / Q000009:adverse effects; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D017510:Protein Folding; D055550:Protein Stability; D058767:Protein Unfolding; D055672:Static Electricity
keywords: active site floppiness; computer simulation; conformational entropy; electrostatic interactions; enzyme activity; fluctuations; heat capacity; network theories; thermostability