Hydrophobic interactions in the formation of secondary structures in small peptides

Abstract

Effects of the attractive and repulsive parts of hydrophobic interactions on α helices and β sheets in small peptides are investigated using a simple atomic potential. Typically, a physical spatial range of attraction tends to favor β sheets, but α helices would be favored if the attractive range were more extended. We also found that desolvation barriers favor β sheets in collapsed conformations of polyalanine, polyvaline, polyleucine, and three fragments of amyloid peptides tested in this study. Our results provide insight into the multifaceted role of hydrophobicity in secondary structure formation, including the α to β transitions in certain amyloid peptides.

Role of side-chain interactions on the formation ofα-helices in model peptides

“…Contact-minimum, desolvation barrier, and solvent-separated minimum of the computed PMF when superposed to distances between i -/ + 1, i -i + 3, and i -i + 4 neighbors provided a qualitative explanation for the observed a-helix content in our simulations. In addition, results from our simulations are consistent with previous studies on the role of desolvation barriers on secondary structure formation [45]. Namely, LJ parameters for which the energy barrier emerges at Cp distances corresponding to i -i + 1 and i -i + 3 neighbors in a-helices are shown to be unfavorable to the formation of these structures.…”

“…Previ ous studies on the role of side-chain interactions in secondary structure formation were either limited to implicit water model [45,[68][69][70], restrained peptide simulations [22], or did not take into account effects due to different length scales [54]. To rationalize variations in a-helix content observed in our simulations we computed effective interactions, i.e., PMF between methane-like particles, that mimic side chains in our modified polyalanine peptides.…”

“…For example, the interaction between methane molecules in water (which are often used as a model for the interaction of nonpolar side chains [38][39][40][41]) is characterized by a global and a local minimum at short (~3 .8 A) and intermediate (~7 A) distances, respectively, separated by an energy barrier related to desolvation effects (at ~5 .7 A) [42], These features affect short range structures in proteins and peptides. For example, in peptides made from aliphatic amino acids it was shown that distances between C p-C p atoms of i -i + 3 and ii + 4 neighbors coincide with the position of desolvation barriers, while C p-C p distances of i -i + 2 neighbors in /I-sheets coincide with the local minimum [22,[43][44][45]. This was shown to play an important role in the propensity of secondary structures studied computationally with implicit water models [45].…”

“…For example, in peptides made from aliphatic amino acids it was shown that distances between C p-C p atoms of i -i + 3 and ii + 4 neighbors coincide with the position of desolvation barriers, while C p-C p distances of i -i + 2 neighbors in /I-sheets coincide with the local minimum [22,[43][44][45]. This was shown to play an important role in the propensity of secondary structures studied computationally with implicit water models [45].…”

α-Helical Structures Drive Early Stages of Self-Assembly of Amyloidogenic Amyloid Polypeptide Aggregate Formation in Membranes

“…Using a simple model, Dias et al69 have shown that β-sheets, since they have the ability to lower hydrophobic energy, tend to be the favored ones in solution – this has also been seen in many simulations3132333435. In a membrane environment, however, the free energy difference between α-helices and β-sheet may become much smaller, although the conformations are separated by free energy barrier that can be large; here, we saw only a small increase in β-sheet formation even at an elevated temperature.…”