Induced fit, conformational selection and independent dynamic segments: an extended view of binding events

Abstract

Single molecule and NMR measurements of protein dynamics increasingly uncover the complexity of binding scenarios. Here we describe an extended conformational selection model which embraces a repertoire of selection and adjustment processes. Induced fit can be viewed as a subset of this repertoire, whose contribution is affected by the bondtypes stabilizing the interaction and the differences between the interacting partners. We argue that protein segments whose dynamics are distinct from the rest of the protein ('discrete breathers') can govern conformational transitions and allosteric propagation that accompany binding processes, and as such may be more sensitive to mutational events. Additionally, we highlight the dynamic complexity of binding scenarios as they relate to events such as aggregation and signalling, and the crowded cellular environment. The induced fit and the original conformational selection modelsThe prevailing view of binding mechanisms has evolved from the early 'lock-and-key' hypothesis [1] to the now popular 'induced fit' model [2]. According to the induced fit scenario, the interaction between a protein and a rigid binding partner induces a conformational change in the protein. However, several systems follow the 'conformational selection' (or, with a different nomenclature, population selection, fluctuation fit, selected fit) paradigm, where among the conformations of the dynamically fluctuating protein the ligand selects the one, which is compatible with binding, and shifts the conformational ensemble towards this state. Selective binding to a single conformation in the ensemble was suggested by Straub as early as 1964 [3]; initial experimental evidence for the hypothesis came from Zavodszky et al. [4] in 1966. Over twenty five years later, in a landmark paper, Frauenfelder, Sligar and Wolynes [5] described the energy landscape of proteins, which in 1999 led to the generalized concept of 'conformational selection and population shift' [6,7]. The observed widespread occurrence of such conformational selection phenomena and their importance in functional scenarios is increasingly supported by X-ray and cryo-electron microscope images, kinetics studies, extensive single molecule fluorescence and in particular, NMR data showing a repertoire of conformational states of unliganded proteins reflecting in vivo occurrences, including conformations corresponding to the bound form [8][9][10].The duality of the induced fit and the original conformational selection models resembles the model pair of the Koshland-Nemethy-Filmer (KNF, [11]) and the Monod-Wyman-Changeux (MWC) models [12] which explain allosteric interactions. Both models describe the allosteric effect as a binding event at one site, which induces a conformational change affecting the activity at another site. However, the KNF-model views the conformational change as a consequence of allosteric binding, whereas the MWC-model describes the conformational change as an allosteric ligand-induced shift of the equilibrium of two, pre-existing...

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