Tipping the Scale from Disorder to Alpha-helix: Folding of Amphiphilic Peptides in the Presence of Macroscopic and Molecular Interfaces

Abstract

Secondary amphiphilicity is inherent to the secondary structural elements of proteins. By forming energetically favorable contacts with each other these amphiphilic building blocks give rise to the formation of a tertiary structure. Small proteins and peptides, on the other hand, are usually too short to form multiple structural elements and cannot stabilize them internally. Therefore, these molecules are often found to be structurally ambiguous up to the point of a large degree of intrinsic disorder in solution. Consequently, their conformational preference is particularly susceptible to environmental conditions such as pH, salts, or presence of interfaces. In this study we use molecular dynamics simulations to analyze the conformational behavior of two synthetic peptides, LKKLLKLLKKLLKL (LK) and EAALAEALAEALAE (EALA), with built-in secondary amphiphilicity upon forming an alpha-helix. We use these model peptides to systematically study their aggregation and the influence of macroscopic and molecular interfaces on their conformational preferences. We show that the peptides are neither random coils in bulk water nor fully formed alpha helices, but adopt multiple conformations and secondary structure elements with short lifetimes. These provide a basis for conformation-selection and population-shift upon environmental changes. Differences in these peptides’ response to macroscopic and molecular interfaces (presented by an aggregation partner) can be linked to their inherent alpha-helical tendencies in bulk water. We find that the peptides’ aggregation behavior is also strongly affected by presence or absence of an interface, and rather subtly depends on their surface charge and hydrophobicity.

Adsorption and conformations of lysozyme and α-lactalbumin at a water-octane interface

“…Due to the associated timescales conformational change of proteins at interfaces has been less studied. For small peptides it is possible to examine changes in secondary structure associated with interfacial adsorption within timescales that can be accessed in simulation 29 . To do this for larger proteins it is necessary to use advanced simulation techniques, such as replica exchange 30 or metadynamics 31 .…”

Assembly of Huntingtin headpiece into α-helical bundles

“…The conformational behavior of htt NT closely resembles the LKa14 peptide with the amino acid sequence Ace-(LKKLLKL) 2 -Nme. 64,65 Similar to htt NT , LKa14 also possesses a large hydrophobic moment 63 in the a-helix conformation and lacks a well-defined secondary structure in dilute solution.…”

Examination of the Effect of N‐terminal Diproline and Charged Side Chains on the Stabilization of Helical Conformation in Alanine–based Short Peptides: A Molecular Dynamics Study

“…These results are consistent with those previously reported by Dalgicdir et al which highlight that two synthetic peptides, LKKLLKLLKKLLKL (LK) and EAALAEALAEALAE (EALA), adopt neither random coil nor fully formed a-helical structure in water. [27] Using molecular dynamics simulations, the authors reported that the peptides adopt multiple conformations with short lifetimes in water. [27] As noted from Table 2, the occupancy of a basin is much higher for ion-pair peptides as compare to cationic peptides.…”

“…[27] Using molecular dynamics simulations, the authors reported that the peptides adopt multiple conformations with short lifetimes in water. [27] As noted from Table 2, the occupancy of a basin is much higher for ion-pair peptides as compare to cationic peptides. The occupancy in a basin is 28.5 %, 28.1 % for Ib, IIb, respectively, while the occupancy is only 19.2 %, 19.9 % for Ia, IIa, respectively.…”