Question

A. What is the ? (alpha)- helical dipole and what is the molecular origin of that dipole?

B. Identify two amino acids that are preferred in ? (beta)- sheets. Why might these amino acids be preferred?

C. Peptide bonds are believed to by hydrated by three water molecules, with one hydrogen bond donated from the N-H and two hydrogen bonds being accepted by the lone pairs of electrons in the carbonyl group. Would you expect a significant entropic component to be associated with the formation of secondary structures like alpha-helicies and beta-sheets. Explain.

Answer 1

1.   Since the alpha helix is the most commonly occurring type of secondary structure in proteins, and as there is quite a variation in the frequency of occurrence of the various amino acid residues in alpha helices, mutations within alpha helices are of considerable importance. Alanine is the most stabilizing residue whereas glycine destabilizes the helix relative to alanine by 0.7-0.8 kcal/mol and proline by 3-4 kcal/mol.Therefore a long stretch of alpha helix substituted by alanine gives a more stable protein. The alignment of dipoles of the polypeptide backbone parallel to the axis of an alpha helices causes a net dipole moment with its positive pole at the amino terminus and negative pole at the carboxy terminus.

MOLECULAR ORIGIN

Throughout the scientific literature on protein research of the last thirty years, the ?-helix dipole is
mentioned in a number of cases where its partial charge on both the C-terminal and the N-terminal
ends is thought to be involved in various biological processes on a molecular level. In order to
understand the cause of this dipole moment, one must look at the structure and the geometry of the
?-helix. The ?-helix is a right handed coiled structure. Each amino acid makes a turn of about 100
degrees and hence it requires 3.6 residues to make a full turn. Amino acids that wind around the axis form hydrogen bounds with each other. The N-H group of each amino acid forms a hydrogen bond with the C=O of the amino
acid that is located four places earlier in the helix. The vast number of hydrogen bonds that is formed is actually the
underlying reason for the forming of this secondary protein structure. Although the principles behind the occurrence of the
helix dipole have been described earlier, its role in protein structure and function was first reviewed by Hol in 1985. He
states that the helix dipole originates in the dipole of the individual peptide unit. The charge distribution within such a
unit is pictured in Figure 1. Its direction is parallel to the N-H and C=O bonds. It has been shown that in an ?-helix around
97% of all peptide dipole moments point in the direction of the helix axis, the dipole is therefore quite insensitive to the ? and ? angles. The C=O groups are in a slightly upward direction (toward the C-terminus) and the N-H groups are in a downward direction (toward the N-terminus) and this gives rise to a small dipole. The aggregate effect of all individual dipoles in an ?-helix is a negative dipole moment at the C-terminal end, and a positive dipole moment at the N-terminal end of the helix. The dipole moment of an individual peptide unit is about 3,46 D which equals 0,72 e