Hydrogen sulfide concentration in the milieu of the hydrated alanine dipeptide determines its polyproline II-beta propensity: Main chain contribution to the energetic origin of the formation of amyloid.

In view of the observation that the concentration of hydrogen sulfide in brains with Alzheimer's disease (AD) is lower than that in normal brains and in line with our previous studies indicating that additional content in the aqueous environment (milieu) of a peptide can change its local energetic preference from a polyproline II (P) to a β conformation (and therefore its tendency to form the β-chain structures that lead to the amyloid plaques associated with the disease), we have studied the effect of H S concentration on such propensity in a simple model peptide, the alanine dipeptide (ADP). The two concentration states are represented by ADP(H O) (H S) and ADP(H O) (H S) . Ab initio calculations of these structures show that the lowest energy of the former is a β conformation while that of the latter is a P, mirroring the observed AD results and strengthening our proposal that amyloid diseases are better viewed in the context of a protein milieu-folding paradigm.

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

Extending our earlier analogous study of the alanine dipeptide (ADP), we have now analyzed the effect of the external environment on the polyproline II (P) and β relative energies, the P/β propensity, of the alanine tripeptide (ATP). Ab initio calculations of ATP(HO) and ATP(HO)(HCl) exhibit the same propensity inversion as in ADP: in the pure water case the PP conformation is favored while the addition of the HCl molecule results in the ββ conformation being of lower energy. A comparison, following an intermediate insertion and departure of an HCl molecule, shows that the energy of a hydrogen-bonded (HO)βATP::βATP(HO) structure is lower than that of the sum of two separate PP systems, i.

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

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.

Water interaction differences determine the relative energetic stability of the polyproline II conformation of the alanine dipeptide in aqueous environments.

Although subsequent studies have provided extensive support for the 1968 Tiffany and Krimm proposal (Biopolymers 6, 1379) that the polyproline II (PPII) conformation is a significant component of the structure of unordered polypeptide chains, two issues are still not fully resolved: the PPII persistence length in a chain and the source of its relative stability with respect to the β-conformation. We examine the latter question by studying the B97-D/6-31++G(**) energy, in the absence and presence of a reaction field, of the alanine dipeptide hydrated by various amounts of explicit waters and resolving this into its three components: the energies of the individual solvated peptides and water structures plus the interaction energy involving them. We find that the relative stability of the PPII conformation is determined mainly by the difference in the interaction energies of the water structures in the near-peptide layers.

Conformation dependence of the DαDα stretch mode in peptides: Side-chain influence in dipeptide structures.

We have shown by theoretical studies of alanine peptides that the C(α)D(α) stretch frequency could be particularly useful for determining peptide structure because of its sensitivity to the ϕ,ψ torsion angles at the C(α) atom. To demonstrate that this is a robust methodology worthy of experimental exploration, we have also shown that this mode is even more determinative of conformation in aqueous solution, mainly as a result of the development of differential C(α)--D(α)···O(water) interactions. As further assurance, we now determine the influence of the side chain on this band, showing for aliphatic, a polar, and an aromatic side chains that the dependence is minor and explaining why this is also expected for other side chains.

Conformation dependence of the C(alpha)D(alpha) stretch mode in peptides. II. explicitly hydrated alanine peptide structures.

Our previous studies of the potential utility of the C(alpha)D(alpha) stretch frequency, nu(CD), as a tool for determining conformation in peptide systems (Mirkin and Krimm, J Phys Chem A 2004, 108, 10923-10924; 2007, 111, 5300-5303) dealt with the spectroscopic characteristics of isolated alanine peptides with alpha(R), beta, and polyproline II structures. We have now extended these ab initio calculations to include various explicit-water environments interacting with such conformers. We find that the structure-discriminating feature of this technique is in fact enhanced as a result of the conformation-specific interactions of the bonding waters, in part due to our finding (Mirkin and Krimm, J Phys Chem B 2008, 112, 15268) that C(alpha)--D(alpha).

Peptide C(alpha)D(alpha) stretch frequencies in a hydrated conformation are perturbed mainly by C(alpha)-D(alpha)...O hydrogen bonding.

We have shown (J. Phys. Chem.

Conformation dependence of the CalphaDalpha stretch mode in peptides. 1. Isolated alanine peptide structures.

Ab initio normal mode calculations have been performed on isolated alanine di- through octa-(i.e., blocked) peptides in uniform alphaR, beta, and polyproline II conformations to determine how the CalphaDalpha stretch mode, which has been proposed as a possible determinant of the varphi,psi conformation at the Calpha atom (Mirkin, N.

Potential energy functions: from consistent force fields to spectroscopically determined polarizable force fields.

We review our methodology for producing physically accurate potential energy functions, particularly relevant in the context of Lifson's goal of including frequency agreement as one of the criteria of a self-consistent force field. Our spectroscopically determined force field (SDFF) procedure guarantees such agreement by imposing it as an initial constraint on parameter optimization, and accomplishes this by an analytical transformation of ab initio "data" into the energy function format. After describing the elements of the SDFF protocol, we indicate its implementation to date and then discuss recent advances in our representation of the force field, in particular those required to produce an SDFF for the peptide group.