Conformational properties of central nervous system myelin basic protein, β‐endorphin, and β‐lipotropin in water and in the presence of anionic lipids

Abstract

SynopsisConformational properties have been examined for three proteins which are disordered when dissolved in water but become partially ordered in the presence of anionic lipids. The three proteins, which play important roles in the central nervous system, are myelin basic protein, P-endorphin, and P-lipotropin. When evaluated using matrix methods, the helical content of each protein is predicted to be vanishingly small in water, in agreement with experiment. Unperturbed root-mean-square radii of gyration are also evaluated for these proteins in water using generator matrices, which have seen wide application to synthetic polymers. Agreement between computed and measured dimensions is found to be excellent. Having successfully described the conformations of myelin basic protein, P-endorphin, and 0-lipotropin in water, attention is then directed to the changes induced upon interaction with anionic lipids or detergents. Computations predict an increase in helical content, with numerical results being in quite good agreement with experimental observations using several anionic lipids. Examination of the helix-propagation-probability profiles reveals an interesting feature of regions where this probability is high. When folded into a a-helix, these regions show one surface where the only side chains are hydrophobic. Charged side chains (with positive charges predominating) are found on the other surface of the helical segment. The arrangement of side chains on these helices is thus well suited to promote favorable interactions with a membrane containing anionic lipids. Examples of the occurrence of these helices are provided by amino acid residues 13-25 and 130-157 in myelin basic protein and residues 17-29 in &endorphin.Several proteins of intense current interest are essentially disordered in water but become partially ordered in the presence of anionic lipids. The helical content of these proteins in water is poorly described1,2 by popular empirical predictive method^^-^ based on the measured properties of globular proteins in the crystalline state. That such is the case is hardly surprising. In the disordered state each amino acid residue is exposed to solvent, while in the globular state many amino acid residues are shielded from the solvent. Since the helix-forming tendency of the various amino acid residues is well known to be solvent dependent, it is to be expected that any empirical method designed to treat globular proteins will fail if applied t o proteins which are substantially disordered.

Cleavage of Rabbit Myelin Basic Protein by Thrombin

“…The thrornbic peptides (1-31), (64-95), and (129-160) encompass sequences that were predicted by Martenson (1981) to undergo coil -+ helix transitions in the presence of anionic lipids, on the basis of secondary structure-predicting algorithms that used the known structures of globular proteins as a data base. Mattice and Robinson (1981), using a matrix method with parameters derived from conformational energy calculations or experimental measurements performed on dilute solutions of simple polypeptides, predicted coil -+ helix transitions in sequences 10-25 and 128-155. Experimental tests of these predictions should now be possible.…”

Structural Aspects of the Interaction of peptidyl‐glycylleucine‐carboxyamide, a Highly Potent Antimicrobial Peptide from Frog Skin, with Lipids

“…The helix probability for each residue was calculated with a computer program written in our laboratory, to apply the method of Mattice and coworkers (Mattice and Robinson, 1981 ;Hamed et al, 1983). A series of 3 x 3 matrices was constructed to calculate the helical probability of each residue in water or in anionic detergents, while 13 X 13 matrices were constructed to calculate each residue's helical probability in zwitterionic lipids.…”

Inhibition of virus‐induced cell fusion by apolipoprotein A‐I and its amphipathic peptide analogs

“…We also synthesized additional peptide analogs expected to show a greater helixforming propensity, based on helix-probability calculations [23] , and these included: [G1ul,*, Leu11J7 ll8A and [Glu"', All the peptides were synthesized by solidphase synthesis method, cleaved from the resin, and purified by HPLC. The analytical HPLC profiles of the purified peptides are shown in Figure 5.…”