Rigidity versus flexibility: the dilemma of understanding protein thermal stability

• Published in: The FEBS journal Vol. 282; no. 20; pp. 3899 - 3917
• Main Authors: Karshikoff, Andrey, Nilsson, Lennart, Ladenstein, Rudolf
• Format: Journal Article
• Language: English
• Published: England Published by Blackwell Pub. on behalf of the Federation of European Biochemical Societies 01.10.2015; Blackwell Publishing Ltd
• Subjects: active site floppiness; active sites; Animals; Biocatalysis; Biophysics; Catalytic Domain; Cold Temperature - adverse effects; computer simulation; conformational entropy; electrostatic interactions; engineering; Entropy; enzyme activity; Enzyme Stability; Enzymes; fluctuations; heat; heat capacity; heat tolerance; Hot Temperature - adverse effects; Humans; Medicin och hälsovetenskap; Models, Molecular; molecular dynamics; network theories; Protein Conformation; Protein Folding; Protein Stability; Protein Unfolding; Proteins; scaffolding proteins; Static Electricity; temperature; thermal stability; thermostability; active site floppiness; conformational entropy; fluctuations; thermostability; enzyme activity; heat capacity; computer simulation; network theories; electrostatic interactions
• ISSN: 1742-464X; 1742-4658; 1742-4658
• DOI: 10.1111/febs.13343

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.