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The inverted free energy landscape of an intrinsically disordered peptide by simulations and experiments.

Granata D, Baftizadeh F, Habchi J, Galvagnion C, De Simone A, Camilloni C, Laio A, Vendruscolo M - Sci Rep (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: International School for Advanced Studies (SISSA), 34136 Trieste, Italy.

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.

No MeSH data available.


Related in: MedlinePlus

Characterization of the high free energy structures of the Aβ40 peptide.Representative conformations sampled during the simulations are shown at increasing values of free energy with respect to the global disordered minimum. On the left we report the average values of radius of gyration and secondary structure population for the whole ensemble and for difference slices in the free energy with a width of 6 kJ/mol (see also Figs 3 and 4). For increasing free energies, Aβ40 becomes more structured by populating both α-helical and β-sheet conformations.
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f2: Characterization of the high free energy structures of the Aβ40 peptide.Representative conformations sampled during the simulations are shown at increasing values of free energy with respect to the global disordered minimum. On the left we report the average values of radius of gyration and secondary structure population for the whole ensemble and for difference slices in the free energy with a width of 6 kJ/mol (see also Figs 3 and 4). For increasing free energies, Aβ40 becomes more structured by populating both α-helical and β-sheet conformations.

Mentions: 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). As expected from the intrinsically disordered nature of Aβ40 the global minimum in this free energy landscape corresponds to an ensemble of highly disordered structures, with only a few transient tertiary contacts and almost no secondary structure elements. Remarkably, however, we also found that at higher free energies the free energy landscape includes a wide variety of partially structured conformations. The free energy of these partially folded conformations is in many cases only 8–10 kJ/mol higher than that of the global minimum, indicating that their populations are not negligible. Moreover, these structures are characterized by several different topologies (Figs 1 and 2) including α-helixes and β-sheets in several different combinations. These structures do not correspond to significant local free energy minima, as shown in Fig. 1. Indeed, the free energy landscape resembles a wide basin, without any sizable free energy barrier, where all the states are kinetically committed to the disordered free energy minimum and can exchange rather rapidly among each other.


The inverted free energy landscape of an intrinsically disordered peptide by simulations and experiments.

Granata D, Baftizadeh F, Habchi J, Galvagnion C, De Simone A, Camilloni C, Laio A, Vendruscolo M - Sci Rep (2015)

Characterization of the high free energy structures of the Aβ40 peptide.Representative conformations sampled during the simulations are shown at increasing values of free energy with respect to the global disordered minimum. On the left we report the average values of radius of gyration and secondary structure population for the whole ensemble and for difference slices in the free energy with a width of 6 kJ/mol (see also Figs 3 and 4). For increasing free energies, Aβ40 becomes more structured by populating both α-helical and β-sheet conformations.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4620491&req=5

f2: Characterization of the high free energy structures of the Aβ40 peptide.Representative conformations sampled during the simulations are shown at increasing values of free energy with respect to the global disordered minimum. On the left we report the average values of radius of gyration and secondary structure population for the whole ensemble and for difference slices in the free energy with a width of 6 kJ/mol (see also Figs 3 and 4). For increasing free energies, Aβ40 becomes more structured by populating both α-helical and β-sheet conformations.
Mentions: 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). As expected from the intrinsically disordered nature of Aβ40 the global minimum in this free energy landscape corresponds to an ensemble of highly disordered structures, with only a few transient tertiary contacts and almost no secondary structure elements. Remarkably, however, we also found that at higher free energies the free energy landscape includes a wide variety of partially structured conformations. The free energy of these partially folded conformations is in many cases only 8–10 kJ/mol higher than that of the global minimum, indicating that their populations are not negligible. Moreover, these structures are characterized by several different topologies (Figs 1 and 2) including α-helixes and β-sheets in several different combinations. These structures do not correspond to significant local free energy minima, as shown in Fig. 1. Indeed, the free energy landscape resembles a wide basin, without any sizable free energy barrier, where all the states are kinetically committed to the disordered free energy minimum and can exchange rather rapidly among each other.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: International School for Advanced Studies (SISSA), 34136 Trieste, Italy.

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.

No MeSH data available.


Related in: MedlinePlus