Solvent effects on the conformational transition of a model polyalanine peptide

Abstract

We have investigated the folding of polyalanine by combining discontinuous molecular dynamics simulation with our newly developed off-lattice intermediate-resolution protein model. The thermodynamics of a system containing a single Ac-KA 14 K-NH 2 molecule has been explored by using the replica exchange simulation method to map out the conformational transitions as a function of temperature. We have also explored the influence of solvent type on the folding process by varying the relative strength of the side-chain's hydrophobic interactions and backbone hydrogen bonding interactions. The peptide in our simulations tends to mimic real polyalanine in that it can exist in three distinct structural states: ␣-helix, ␤-structures (including ␤-hairpin and ␤-sheet-like structures), and random coil, depending upon the solvent conditions. At low values of the hydrophobic interaction strength between nonpolar side-chains, the polyalanine peptide undergoes a relatively sharp transition between an ␣-helical conformation at low temperatures and a random-coil conformation at high temperatures. As the hydrophobic interaction strength increases, this transition shifts to higher temperatures. Increasing the hydrophobic interaction strength even further induces a second transition to a ␤-hairpin, resulting in an ␣-helical conformation at low temperatures, a ␤-hairpin at intermediate temperatures, and a random coil at high temperatures. At very high values of the hydrophobic interaction strength, polyalanines become ␤-hairpins and ␤-sheet-like structures at low temperatures and random coils at high temperatures. This study of the folding of a single polyalanine-based peptide sets the stage for a study of polyalanine aggregation in a forthcoming paper.Keywords: polyalanine; ␣-␤ transition; secondary structures; solvent conditions; discontinuous molecular dynamics Small peptides undergo a spontaneous reversible disorderto-order transition to a unique, three-dimensional equilibrium structure such as an ␣-helix or a ␤-structure when exposed to favorable physiological conditions. The information necessary to drive this folding transition is universally accepted to be encrypted solely within the linear amino acid sequence (Anfinsen 1973;Anfinsen and Scheraga 1975). However, experiments indicate that many peptides can be folded into alternative stable structures by changing the solution conditions (Rosenheck and Doty 1961;Kabsch and Sander 1984;Mutter and Hersperger 1990;Mutter et al. 1991;Zhong and Johnson 1992;Cohen et al. 1993;Waterhous and Johnson 1994). For example, many peptides are well known to undergo a sharp helix-coil transition as the temperature is increased (Poland and Scheraga 1970;Rohl and Baldwin 1998). Furthermore, the conformational transition between the ␣-helix and ␤-structure is greatly influenced by solvent conditions, including the pH (Mutter and Hersperger 1990;Cerpa et al. 1996;Tuchscherer et al. 1999), the temperature (Cerpa et al. 1996;Fukushima 1996;Zhang and Rich 1997), the salt or organic cosolvent ...

Transitions between secondary structures in isolated polyalanines

“…These results are consistent with experimental measurements [38] and also with previous theoretical suggestions from other groups [39][40][41]. Here we focus on the α-helix ↔ β-sheet interconversion, which we attempt to characterize in terms of specific order parameters.…”

Hydrophobic interactions in the formation of secondary structures in small peptides

“…Our results show that both a repulsive db and a physically realistic range of cm attraction of ∼5.0Å between methyl or methylene groups tend to favor β over α structures, at least for the polyalanine, polyvaline, and polyleucine chains we have studied. This finding may help to assess prior studies that used effective ranges of cm attraction as large as 6.5Å [31,32]. db's arise from empty spaces created by water exclusion between hydrophobic groups [37][38][39][40]42] and are the hallmark of interactions between nonpolar groups [33,34,[36][37][38][39][40][41][42][43] that are partially exposed to water.…”

“…An early simulation of a 12mer polyalanine indicated that its ground state was an α helix in vacuum and a β hairpin in aqueous solution [30]. However, subsequent simulations of aqueous short hydrophobic-polar [31] and polyalanine [32] peptides using different potential functions predicted an α-helical ground state except for very high hydrophobic interaction strengths [32].…”

“…We also considered desolvation barrier (db) effects as they are critical in protein energetics [33][34][35][36][37][38][39][40][41][42][43]. db effects were neglected in many implicit-water potential functions [31,32] despite studies showing its importance for protein structure prediction [44]. For polyalanine, we found that sidechains subjected to hydrophobic interactions in α helices are constrained to the db region and thus are disfavored [45,46].…”

One‐Dimensional Gold Nanoparticle Arrays by Electrostatically Directed Organization Using Polypeptide Self‐Assembly

“…Hydrophobic interactions and hydrogen bonding are the primary driving forces that cause such assembly in 17H6; hairpin substructures have also been reported for other alanine-rich sequences. [48][49][50] Hydrophobic interactions promote the exclusion of water and other hydrophilic species by collapse of the hydrophobic alanine residues. Hydrogen bonding within the β sheets stabilizes this structure, which incorporates more 17H6 monomer units in a similar manner and leads to fibril axial fibril growth.…”