NSTI Nanotech 2009

Thermodynamic basis for the design of efficient conformational change-based biosensors

A. Vallee-Belisle, F. Ricci, K.W. Plaxco
University of California, Santa Barbara, US

Keywords: biosensors, ligand-induced conformational change, thermodynamics, rational optimization, molecular beacons


Recent years have seen the development of a number of biosensor platforms based on binding-induced conformational changes in oligonuclotides, polypeptides and proteins (Fig. 1). Examples include both optical and electrochemically-interrogated molecular beacons for the detection of oligonucleotides [1], aptamer-beacons for the detection of proteins, small molecules and inorganic ions [2], and a number of sensors based on binding-induced conformational changes in proteins [3]. A key and hitherto poorly explored aspect of these sensors is that their performance is largely dictated by a compromise in their switching thermodynamics. Namely, while the conformational equilibrium underlying the sensor should favor the non-binding, non-signaling state in order to optimize the population shift observed upon target binding, over-stabilization of the non-binding state depopulates the binding-competent conformation and thus decreases the sensorís affinity for its target (see Fig. 1). In my presentation, I will describe a universal three-state mathematical model that simulates the readout of conformational change-based biosensors and provides guidance for optimizing their switching thermodynamics. As a proof of principle, I will demonstrate that, consistent with our model, the gain of a representative molecular beacon can be varied by more than 4 orders of magnitude by altering the stability of its stem. These findings may be applicable to enhance the sensitivity and the detection limit of all conformational change-based biosensors currently in use.
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