Friday, August 07, 2009

molecular switches

Natural receptors and newly developed biosensors such as aptamer sensors share the key feature that they undergo structural change during binding of a ligand.

Kevin Plaxco and co-workers at Santa Barbara have now shown in a PNAS paper released this week that a simple thermodynamic model involving only three states can explain the response of such receptors or sensors. The states involved are (1) nonbinding state, (2) binding competent state, and then (3) ligand-bound state, with a "switch" equilibrium constant governing the change from (1) to (2) and a binding constant the move from (2) to (3).

From the group's press blurb:

In their PNAS paper, Alexis Vallée-Bélisle of UCSB, collaborator Francesco Ricci of the University of Rome Tor Vergata, and senior author Prof. Kevin Plaxco, describe and test a simple mathematical “population-shift” model that will allow biotech researchers to fine-tune the ease with which artificial biomolecular switches can be “flipped”. It also sheds light on how natural biomolecular switches evolved.

Specifically, they show that switching reflects a fundamental trade-off. On the one hand, in the absence of the input signal, the “off” state of the switch must be more stable than its “on” state in order to allow more switches to occupy the “off” state where they are poised to respond to the target and generate a large output signal. On the other hand, if the “off” state is too stable the switch will require much more input signal before it will flip. Optimal switch performance –optimal sensitivity to the switching agent- is thus achieved when the off state is neither too stable nor too unstable. Vallée-Bélisle’s population-shift model describes the relationship between off-state stability and switch sensitivity, thus providing researchers an approach to rationally optimize the performance of artificial switches, and providing insights into the evolution of their naturally occurring analogs.

Thermodynamic basis for the optimization of binding-induced biomolecular switches and structure-switching biosensors

Alexis Vallée-Bélisle, Francesco Riccia, and Kevin W. Plaxco

Published online before print August 5, 2009, doi: 10.1073/pnas.0904005106

abstract and link to PDF

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