Abstract
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.
Highlights
Form of the Aβ 40 peptide, a 40-residue protein fragment associated with Alzheimer’s disease, which has been extensively studied experimentally and computationally[29,30,31,32,33,34,35,36,37,38,39,40]
Our results indicate that the global minimum in the free energy landscape of the Aβ 40 peptide is represented by highly unstructured conformations, almost completely devoid of persistent secondary and tertiary elements
From the molecular dynamics simulations described above we obtained a free energy landscape projected on three variables, the β -sheet content, the α -helical content and the number of hydrophobic contacts (Fig. 1)
Summary
Form of the Aβ 40 peptide, a 40-residue protein fragment associated with Alzheimer’s disease, which has been extensively studied experimentally and computationally[29,30,31,32,33,34,35,36,37,38,39,40]. To characterize the structure and thermodynamics of this peptide, we extend to intrinsically disordered proteins a recently introduced approach that enables the characterisation of the free energy landscape of folded proteins by using NMR measurements to accelerate the conformational sampling[44] in explicit solvent all-atom simulations In this strategy, NMR chemical shifts are used to define a collective variable that is used in a bias-exchange metadynamics framework[45]. A possible consequence of these results is that for increasing temperatures, when higher free energy states becomes more populated, intrinsically disordered proteins become more structured - and more compact - as their high free energy states are characterized by the presence of more secondary and tertiary interactions than their native states We show that this scenario is realized for the Aβ 40 peptide by using a range of experimental biophysical techniques, which enable us to detect an overall structuring and compaction with increasing temperatures. We provide a thermodynamic analysis of the interplay between entropy and enthalpy that underlies this phenomenon
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