Proline conformational analysis

Haasnoot, C. A. G., De Leeuw, F. A. A. M., De Leeuw, H. P. M., Altona, C. Relationship between proton-proton NMR coupling constants and substituent electronegativities. III. Conformational analysis of proline rings in solution using a generalized Karplus equation. Biopolymers 1981, 20,1211-1245. 

The most elaborate use of MM calculations in the LIS analysis was described by DeTar and Luthra (298). Their approach was based on the traditional relative shift method, wherein lanthanide parameters are adjusted to give optimum agreement with the observed relative LIS values. Based on their previous analysis of proline conformations (228), they determined that A-acetylproline methyl ester (71) exists in CDQ3 as a 60 40 mixture of half-chair and envelope conformations by simultaneously adjusting the substrate geometries and the conformer mole fractions, in addition to the lanthanide parameters (298). 

In this chapter we give an overview of the large number of naturally or chemically substituted proline derivatives, their conformational analysis and role in native polypeptides, with an emphasis on their impact on collagen-like structures as well as mimetics for the induction of various turn conformations. 

These conclusions were drawn from the X-ray structures of some of the hydrox-ylated prolines and related N-acetyl methyl ester derivatives [39,40] as well as from the thermodynamic parameters obtained by NMR conformational analysis of the model compounds Ac-Pro -OMe, with Pro corresponding to 1-4 [15,21,32], and Ac-Phe-Pro -NHMe, with Pro being 1-5 (Tables 11.1 and 11.2) [41], While O-acetylation or O-trifluoroacetylation of the 4-hydroxyproline increases the inductive effects [40], and thus stabilizes the O-exo pucker and trans-conformation of aminoacyl-Hyp bonds, unfavorable steric interactions reduce these effects in terms of triple-helix induction and stability [40]. In addition, Table 11.2 reports the thermodynamic parameters of (3R,4S)-Dhp (6) which displays a similar behavior... 

The conformational analysis of several linear proline-containing hormones has been considerably aided by 1 3C nmr studies. The ratio of cis- and trans-isomers and the spin lattice relaxation times of thyrotropin-releasing factor or hormone (TRF or TRH), L-pyro-glutamyl-L-histidyl-L-prolinamidc, in deuterium oxide, deuterated dimethyl sulfoxide and deuterated pyridine have been determined... 

Venkatachalam [36] has done a qualitative conformational analysis of cyclic tri-proline. The dihedral angles of the conformation which he predicts differ markedly from the ones calculated by us. In Venkatachalam s model the closure of the backbone ring requires adjustment of the torsional angles about the peptide bonds while the proline rings are planar. It turns out that this is the wrong choice it is the peptide bonds which remain planar, and the torsional angles about the N—C bonds adjust to close the backbone ring. 

Chyraotrypsin inhibitor 2 (CI2) folds rapidly by simple two-state kinetics that is, D N, with a r1/2of 13 ms.18,19 CI2 is a small 64-residue protein that has all its peptidyl-proline bonds in the favorable trans conformation.20 (There are, of course, additional slow cis —> trans peptidyl-prolyl isomerization events, which account for about 20-30% of the refolding amplitudes.) The occurrence of two-state kinetics does not prove that there are no intermediates on the folding pathway there could be intermediates that are present at high energy and are kineti-cally undetectable (see section B4). Two-state behavior has subsequently been found for many other small proteins. The simplicity of two-state folding kinetics provides the ideal starting point for the analysis and illumination of the basic principles of folding. 

In related model complex studies, Isied and coworkers, have examined photo-induced (or pulse-radiolytically initiated) electron-transfer processes in which a polypyridine-ruthenium(II) complex is linked by means of a 4-carboxylato,4 -methyl,2,2 -bipyridine ligand and a polyproline chain to a [Co(NH3)5] + or [(-NH-py)Ru (NH3)5] acceptor. Chains composed of from zero to six cis-prolines have been examined. The apparent distance dependence of the electron-transfer rate constant, corrected for variations in the solvent reorganizational energy, seems to exhibit two types of distance dependence, 0.7-1A for short chains and /3 a0.3 A for long chains. A very detailed theoretical analysis of electron transfer in the complexes with four proline linkers has indicated that the electronic coupling is sensitive to conformational variations within the proline chain. ... 

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