The inverted free energy landscape of an intrinsically disordered peptide by simulations and experiments.
The free energy landscape theory has been very successful in rationalizing the folding behaviour of globular proteins, as this representation provides intuitive information on the number of states involved in the folding process, their populations and pathways of interconversion. We extend here this formalism to the case of the Aβ40 peptide, a 40-residue intrinsically disordered protein fragment associated with Alzheimer's disease. By using an advanced sampling technique that enables free energy calculations to reach convergence also in the case of highly disordered states of proteins, we provide a precise structural characterization of the free energy landscape of this peptide. We find that such landscape has inverted features with respect to those typical of folded proteins. While the global free energy minimum consists of highly disordered structures, higher free energy regions correspond to a large variety of transiently structured conformations with secondary structure elements arranged in several different manners, and are not separated from each other by sizeable free energy barriers. From this peculiar structure of the free energy landscape we predict that this peptide should become more structured and not only more compact, with increasing temperatures, and we show that this is the case through a series of biophysical measurements.
International School for Advanced Studies (SISSA), 34136 Trieste, Italy.|Institute of Computational and Molecular Science (ICMS), Temple University, Philadelphia, PA 19122, USA.
Daniele
D
Granata
International School for Advanced Studies (SISSA), 34136 Trieste, Italy.|Department of Chemical Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.
Fahimeh
F
Baftizadeh
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Johnny
J
Habchi
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Celine
C
Galvagnion
Division of Molecular Biosciences, Imperial College London, London SW7 2AZ, UK.
Alfonso
A
De Simone
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Carlo
C
Camilloni
International School for Advanced Studies (SISSA), 34136 Trieste, Italy.
Alessandro
A
Laio
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Michele
M
Vendruscolo
D002850:Chromatography, Gel; D002942:Circular Dichroism; D064267:Intrinsically Disordered Proteins / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D013816:Thermodynamics
D064267:Intrinsically Disordered Proteins