Other species in the aqueous environment of a peptide can invert its intrinsic solvated polyproline II/beta propensity: Implications for amyloid formation

Abstract

As we have previously shown, the predominance of the polyproline II conformation in the circular dichroism spectra of aqueous polypeptides is related to its lower energy than that of the beta conformation. To test whether this is still the case in the presence of additional components in the medium, we have calculated the energy difference between these two conformations in an alanine-dipeptide/12-water system without and with the addition of an HCl molecule. We find in the latter case that the beta conformer is of lower energy than the polyproline II. Energy profiles near the minima in both cases also permit conclusions about the relative entropies of these structures. These results emphasize the importance of considering the peptide-plus-medium state as the relevant entity in determining the structural properties of such systems. Such an inversion could be relevant to the formation of amyloid and could thus lead to new strategies for studying its role in the development of neurodegenerative diseases. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 305-311, 2016.

Milieu-Initiated Inversion of the Aqueous Polyproline II/β Propensity in the Alanine Tripeptide: Aggregation Origin of the Onset of Amyloid Formation

“…The result can be inferred from the following energy comparison. We focus on two individual ATP molecules: 1) in a pure aqueous environment both ATPs are preferably in the P 1 P 2 conformation, i.e., "solubilized"; 2) an HCl molecule attaches to one ATP, which then assumes the more favorable β 1 β 2 conformation; to reach the final state we now suppose that the other P 1 P 2 peptide converts to ββ and it hydrogen-bonds (:::) to the β 1 β 2 peptide to form the ATP:::ATP(H 2 O) 38 (HCl) complex, which will lower the energy 4 ; 3) the HCl molecule departs and we compare the total energy of this system with that of 1), the originally separated P 1 P 2 components. The energy of 3) was determined by forming the optimally hydrogen-bonded antiparallel ATP:::PTA pair not certified by peer review) is the author/funder.…”

“…The ATP molecule, CH 3 −CONH−C 1 H(CH 3 )−CONH−C 2 H(CH 3 ) − CONH−CH 3 , hydrated with water was minimized in the following way: 1) the peptide was constructed with the canonical values of ϕ,ψ (P: −75°, 145° and β: −134°, 145°); 2) first-layer waters were added to the ubiquitous peptide hydrogen-bonding positions, i.e., two to the CO and one to the NH, comprising a total of 9 water molecules, and the entire system was minimized; 3) using the new ϕ,ψ as a starting point and adding sufficient waters to complete the second layer, 10 in this case for a total of 19, the system was again totally relaxed and minimized. As before 4 , the global and some local minima of each conformation were determined. For the ATP(H 2 O) 19 (HCl) system, as previously 4 , the HCl was added to the above minimized structures in a variety of ways: as an intact molecule initially located in numerous positions with respect to the water layers and as initially separate ions in various locations and the total system was minimized.…”

“…As before 4 , the global and some local minima of each conformation were determined. For the ATP(H 2 O) 19 (HCl) system, as previously 4 , the HCl was added to the above minimized structures in a variety of ways: as an intact molecule initially located in numerous positions with respect to the water layers and as initially separate ions in various locations and the total system was minimized. In all cases the final structures had separated ions imbedded in the water environment.…”

Milieu-Initiated Inversion of the Aqueous Polyproline II/Beta Propensity in the Alanine Tripeptide: Energetics Origin of the Onset of Amyloid Formation

“…Of course, if both molecules in 1) have HCl entrained and therefore in ββ conformations then the probability of forming an aggregate is enhanced. (The true propensities are obviously determined by the free energies, but if the energy profiles in the ATP cases are similarly shaped, as in the ADP case 4 , implying that the entropies of the two structures are about the same, the free energies will track the enthalpies.) It might be thought that this result is just an abstract theoretical exercise, but there has long been strong x-ray diffraction evidence of its occurrence in low molecular weight synthetic polypeptides, with the formation of cross-beta structures 9 (in which the local peptide chain axis is perpendicular to the global fibril axis), and indeed is a long-known property of proteins 10,11 .…”

“…This value is in line with the result of -1.72 kcal/mol for the comparable ΔE of ADP(H 2 O) 12 4 in indicating the preferred stability of the P 1 P 2 conformation in an all-aqueous environment (even though the energy of an isolated β 1 β 2 structure with the ϕ,ψ of the hydrated structure is 1.28 kcal/mol lower than that of the comparable P 1 P 2 ). Such an energy difference is associated with the different total interaction energies (i.e., peptide-water and water-water) in the two structures 4 , part of which shows up as a difference in total charge on the peptide, in this case -2 me on P 1 P 2 and 37 me on β 1 β 2 (compared to zero for the neutral isolated structures). The inclusion of a PCM reaction field in the calculation does not change the ϕ,ψ appreciably but the ΔE increases to -2.62 kcal/mol and, presumably as a result of the additional effects of polarization and charge transfer 6 through water-peptide hydrogen bonds 7,8 , the relevant peptide charges become more positive, at 28 me and 59 me, respectively.…”