Behavior of amphipathic helices on analysis via matrix methods, with application to glucagon, secretin, and vasoactive intestinal peptide

Abstract

SynopsisA configuration partition function, which incorporates concepts embodied in the amphipathic helix hypothesis, has been formulated for a polypeptide in the presence of zwitterionic phospholipid. An enhanced probability is assigned to helix formation in any region of the polypeptide chain where side chains bearing charges of opposite sign will be situated on the same side of the a-helix but displaced from one another by one turn. This situation will arise when residues i -4 (or i -3) and i bear charges of opposite sign and residues i -4 (or i -3) through i are in a helical state. Illustrative calculations are performed for polypeptide chains in which the generalized nonionic amino acid residue serving as host has Zimm-Bragg parameters of o = lo-*, s = l. These calculations define conditions under which two interacting charged pairs can cooperate in a synergistic helix augmentation even when the two pairs are separated by significantly more than four generalized nonionic amino acid residues. Furthermore, the two interacting charged pairs, as well as the intervening amino acid residues, may become helical as one unit. Significant augmentation in helicity is observed with plausible values for the enhanced probability assigned to helix formation for an interacting pair. This model predicts correctly that glucagon and secretin, but not vasoactive intestinal peptide, undergo a coil-to-helix transition in the presence of zwitterionic phospholipid. This prediction is made with plausible values for the parameter used to express the helicity enhancement. The experimental observation with zwitterionic phospholipids is the direct opposite of that seen for these three peptides in the presence of anionic lipids and detergents. In anionic lipids the amount of induced helicity is in the following order: glucagon < secretin < vasoactive intestinal peptide. Results obtained with these three peptides demonstrate that the nature of the head group of the lipid is important for lipid-protein interaction and that the resulting conformational changes can be rationalized by matrix methods.

Conformational flexibility and biological activity of salmon calcitonin

“…The extension of statistical mechanical theories of the helix-coil transition to include effects of lipids (Mattice & Robinson, 1981;Hamed et al, 1983) correctly predicts the increased helical content of sCT in the presence of lipids the presence and absence of DMPG: 90 µ peptide in 10 mM sodium phosphate buffer, pH 7.0 (X, ---), and in the presence of 2.4 mM DMPG ( , -). Points are the experimentally determined values, and lines are the least-squares best-fit curves for the mixtrues of secondary structures given in Table II.…”

“…Calculation of Helix Probability Profiles. The probability of folding into a helical conformation was calculated for each amino acid residue by the method of Mattice and co-workers (Mattice & Robinson, 1981;Hamed et al, 1983). The statistical weights for each amino acid at 30 °C (Mattice & Robinson, 1981;Hamed et al, 1983) were used to construct a series of 3 X 3 matrices to calculate the helical content in water and SDS and to construct a series of 13 X 13 matrices for the conformation in zwitterionic lipids.…”

“…The probability of folding into a helical conformation was calculated for each amino acid residue by the method of Mattice and co-workers (Mattice & Robinson, 1981;Hamed et al, 1983). The statistical weights for each amino acid at 30 °C (Mattice & Robinson, 1981;Hamed et al, 1983) were used to construct a series of 3 X 3 matrices to calculate the helical content in water and SDS and to construct a series of 13 X 13 matrices for the conformation in zwitterionic lipids. For the peptides in the presence of zwitterionic lipids, a statistical weight of 5 ± = 4 was used for charged residues which were separated by two or three other residues from a charged residue of opposite sign.…”

Structural studies of a baboon (Papio sp.) plasma protein inhibitor of cholesteryl ester transferase

“…It has also been suggested that electrostatic interresidue interactions may play a role in stabilizing the helical structure of lipidbound segments of amphipathic helices~Segrest, 1977; Hamed et al, 1983!. Interresidue salt bridges formed between oppositely charged side chains three or four residues apart have been shown to stabilize a-helical structures by up to 6 kcal0mol0salt-bridgẽ Merutka & Stellwagen, 1991;Lyu et al, 1992!.…”

New Fourier transform infrared based computational method for peptide secondary structure determination. I. Description of method

“…These latter conditions are convenient to study large molecules such as proteins and polypeptides but are completely inadequate in the case of small, flexible molecules like short peptides. It is well known, in fact, that in dilute aqueous solutions disordered populations are particularly favored, while the presence of ordered structures is negligible and, quite often, not detectable 20. On the other hand, conditions that mimic the hydrophobic environment typical of membranes may stabilize secondary structures; this is the reason why peptides are often studied in the presence of organic solvents and/or surfactants like sodium dodecylsulfate,21 even though the interpretation of the FTIR spectra becomes more complicated.…”