| dc.description.abstract | In the first place, the uniqueness of any MEC within a certain region demonstrates the successful incorporation of the hydrogen?bond energy function in a minimization program. In particular, its interpolation with the non?bonded energy has helped retain the smoothness of the energy surface when going from a hydrogen?bonded conformation to a non?hydrogen?bonded one.
The application to di? and tripeptide systems has resulted in conformationally good ?? and ??turns, with some notable features listed below:
a) Absence of short contacts in all the ?? and ??turn MECs.
b) The ??turns can be considered as bends using different criteria (Chou and Fasman, 1977; Ramakrishnan and Soman, 1982).
c) The hydrogen bonds in the ?? and ??turns belong to the moderately good or very good category.
d) Only marginal changes in the peptide parameters of the MECs from the standard values.
Thus, the incorporation of this hydrogen?bond energy function in an energy?minimization program and its subsequent application to model peptide systems have resulted in some unique conformations—such as the presence of both hydrogen bonds in types I and II ??turns. While this is expected in solution, it awaits experimental verification.
In this chapter, the extension of the minimization studies on the basic CHPs was illustrated by taking proline?containing CHPs as an example. Specifically, systems like c(Gly?Pro?Gly)?, c(Pro?Gly)? and c(Gly?Pro?Gly?Gly?D?Pro?Gly) were considered so that all the basic CHP minima worked out earlier (Chapters 4 to 7) could be used as starting points.
All MECs of the Pro?containing CHPs—except c(Gly?Pro?Gly)? in the (?????)? conformation, which shows strain in the ? and ? values—are found to be conformationally good.
Some features of Pro?containing CHPs are:
a) In c(Gly?Pro?Gly)?, MECs with both Pro?Gly and Gly?Pro ??turns are possible. In each of these schemes, the different symmetric and non?symmetric MECs have nearly identical total energies. Conformations having type I or I? ??turns with 4?1 and 3?1 hydrogen bonds in bifurcated form, and type II ??turns with both 4?1 and 3?1 hydrogen bonds, are possible.
b) Two conformations of c(Pro?Gly)? were obtained, though experimental and earlier theoretical studies suggested that only one conformation is likely.
c) Proline residues (L or D) can be successfully accommodated in inversion?symmetric CHPs.
Thus, an analysis of the CHPs provides guidelines useful for understanding CHP conformations. The notable features are:
a) CHPs with symmetry in the sequence tend to adopt structures reflecting this symmetry.
b) CHPs with no sequence symmetry assume conformations composed of different combinations of ??turns, sometimes with near inversion symmetry or completely asymmetric.
c) CHPs with exact two?fold or inversion symmetry consist of identical or inverse ??turns, respectively.
d) Pro residues always occur in the middle positions of ??turns in CHPs.
e) D?residues almost always occupy the middle position of ??turns.
f) The position of Pro in ??turns of CHPs of the type c(X?Pro?Z)? depends on the nature of X and Z, as given in Table 10.6.
g) Only residue combinations allowed by Ramachandran maps occur in types I, II ??turns and their inverses.
For a CHP with a given sequence, all the information above can be used—with the conformations proposed in this thesis—to work out or predict plausible conformations. As more experimental studies become available, their conformational features must be examined to see whether these guidelines hold.
Overview
In this thesis, the accommodation of hydrogen?bonded ?? and ??turns in the backbone of cyclic hexapeptides (CHPs) has been explored using stereochemical criteria and energy calculations. Many CHP minima with different molecular symmetries, conformational characteristics, and hydrogen?bonding schemes were obtained.
The stereochemical favourability of L?Ala and D?Ala residues to occur in these minima was evaluated using the Ramachandran maps. An analysis of available experimental data was presented to formulate simple guidelines for proposing likely conformations.
The conformations worked out in this thesis are closely related to experimentally observed ones in terms of secondary?structure features and hydrogen?bonding schemes. However, not all possibilities proposed have yet been observed experimentally. Some conformations rich in hydrogen bonds may not occur experimentally, yet they offer valuable starting points for understanding plausible peptide conformations.
Some hydrogen?bonding schemes proposed for ??turns in CHPs have indeed been observed in solution. In particular, the coexistence of 4?1 and 3?1 hydrogen bonds in type II ??turns, proposed in this thesis, has been experimentally confirmed.
The conformations of CHPs in the solid state and in solution are not necessarily identical. Difficulties in predicting solution conformations may arise from the fact that NMR spectra average multiple conformers. Nonetheless, model?building studies greatly aid prediction.
It is hoped that the studies in this thesis will contribute to understanding the solution?state conformations of cyclic hexapeptides. | |
