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Downhill Folding Protein Modules as Conformational Rheostats: Roles in Molecular Biology and Applications as Biosensors (MOLRHEOSTAT)
Start date: May 1, 2013, End date: Apr 30, 2018 PROJECT  FINISHED 

Protein folding and function is a perfect arena towards growing the grassroots of quantitative and synthetic biology. This is so because all cellular processes controlled by proteins can ultimately be traced back to physico-chemical properties encoded in their aminoacid sequences. MOLRHEOSTAT is framed within these goals, focusing on the investigation of novel connections between protein folding and function via a multidisciplinary approach that combines experiment (single molecule spectroscopy, high-resolution NMR, protein engineering and design), theory and computer simulations.Conventionally, proteins are portrayed as conformational switches that fold and function by flipping between an on-state (native, active) and an off-state (inactive, unfolded) in response to stimuli. However, last years have witnessed the discovery of protein modules that undergo continuous conformational changes upon unfolding (downhill folding). MOLRHEOSTAT aims at investigating the functional and technological implications of downhill folding. The goal is to determine whether downhill folding modules can be exploited to build conformational rheostats; that is, proteins that continuously modulate a signal or response at the single molecule level by tuning their folding conformational ensemble. Conformational rheostats could open a new realm of applications as synthetic biomolecular devices as well as regulatory mechanisms for controlling complex biochemical processes carried out by macromolecular assemblies. These ideas will be explored on two specific objectives:1) Implementation of a general approach for building high-performance, ultrafast, single-molecule sensors based on downhill protein folding modules.2) Analysis of the roles of conformational rheostats in the regulation of three fundamental processes in molecular biology (coordination in protein networks, DNA sliding and homing-to-target of transcription factors, and molecular springs in macromolecular assemblies).

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