3. Secondary structures are often oriented so that one side faces the outer surf

Question

3. Secondary structures are often oriented so that one side faces the outer surface of a protein and the other faces the interior. Given that each of the three following amino acid sequences forms an -helical stretch of a protein, determine whether each helix is amphipathic (polar on one side and nonpolar on the other), electrically polarized (positively charged on one side and negative on the other), or shows no systematic chemical pattern. For your convenience non-polar amino acids are shaded, and side chains with formal charges at neutral pH are indicated. (I0 points each, 30 total) DLR S N T VE N KISA S EIRL

Explanation / Answer

* Amphipathic helices play a crucial role in mediating the interaction of peptides and proteins with membranes. We have analyzed protein structures for the occurrence of 18residue amphipathic helices. We find several of these helices having average hydrophobic moments and average hydrophobicities that would favor their interaction with membranes. We have analyzed the distribution of net charge, helix length, normalized frequency of occurrence, and propensities of the 20 amino acids in the delineated 18residue helices. We have observed distinct differences in the frequencies of occurrence of polar and hydrophobic amino acids at positions 1–18 in amphipathic and nonamphipathic helices. There are also differences in propensities of the 20 amino acids to occur at positions 1–18 of amphipathic and nonamphipathic helices. Synthetic peptides corresponding to some of these surfaceseeking helices do possess antibacterial and/or hemolytic activities. Knowledge of the distribution of charges in 18residue surfaceseeking amphipathic helices, as well as propensity of occurrence of amino acids at various positions, would be useful inputs in the de novo design of amphipathic peptides.

* The voltage sensor domain (VSD) of the potassium ion channel KvAP is comprised of four (S1–S4) -helix proteins, which are encompassed by several charged residues. Apart from these charges, each peptide -helix having two inherent equal and opposite terminal dipolar charges behave like a macrodipole. The activity of voltage gated ion channel is electrostatic, where all the charges (charged residues and dipolar terminal charges) interact with each other and with the transmembrane potential. There are evidences that the role of the charged residues dominate the stabilization of the conformation and the gating process of the ion channel, but the role of the terminal dipolar charges are never considered in such analysis. Here, using electrostatic theory, we have studied the role of the dipolar terminal charges in aggregation of the S3b–S4 helix pair of KvAP in the absence of any external field (V = 0). A system attains stability, when its potential energy reaches minimum values. We have shown that the presence of terminal dipole charges (1) change the total potential energy of the charges on S3b–S4, affecting the stabilization of the -helix pair within the bilayer lipid membrane and (2) the C- and the N-termini of the -helices favor a different dielectric medium for enhanced stability. Thus, the dipolar terminal charges play a significant role in the aggregation of the two neighboring -helices.

* The helical wheel represents a helix by a projection of the C backbone structure down the helix axis, while the wenxiang diagram represents it more abstractly as a smooth spiral coiled on the plane of the page. Both label the sequence with one-letter amino-acid code at each C position, using different colors or symbols to code the amino-acid properties. Hydrophobic vs hydrophilic amino acids are always distinguished, as the most important property governing helix interactions. Sometimes positively vs negatively charged hydrophilics are distinguished, and sometimes ambiguous amino acids such as glycine (G) are distinguished. Color-coding conventions are various. The helical wheel does not change representation along the helix, while the wenxiang diagram is able to show the relative locations of the amino acids in an -helix regardless of how long it is.

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