1. Peptides containing the sulfonamide transition-state isostere: synthesis and structure of N-acetyl-tauryl-L-proline methylamide
W J Moree, A Schouten, J Kroon, R M Liskamp Int J Pept Protein Res. 1995 Jun;45(6):501-7. doi: 10.1111/j.1399-3011.1995.tb01312.x.
The structure of the sulfonamide isostere-containing peptide N-acetyl-tauryl-proline methylamide 4 was compared to information on the structure of the peptide N-acetyl-beta-alanyl-proline methylamide 6. NMR measurements of the beta-alanine containing peptide 6 showed the presence of two conformations due to cis/trans isomerism of the beta-Ala-Pro amide bond, whereas the sulfonamide-containing peptide 4 appeared in only one conformation. The crystal structure of N-acetyl-tauryl-proline methylamide 4 gave additional evidence for the absence of cis/trans isomerism. The crystals are orthorhombic, space group P2(1)2(1)2(1), Z = 4, F(000) = 592, a = 7.5919(3), b = 10.3822(2), c = 17.1908(7) A, V = 1354.99(8) A3, Dx = 1.359 g cm-3. The oxygen atoms connected to the sulfur take positions similar to both the cis and trans positions of the carbonyl oxygen of an amide. Consequently the tauryl part is placed perpendicular to the proline alpha-C-C(O) bond, giving it an extended conformation in contrast to the cis/trans isomers of N-acetyl-beta-alanyl-proline methylamide 6.
2. Unconventional N-H…N Hydrogen Bonds Involving Proline Backbone Nitrogen in Protein Structures
R N V Krishna Deepak, Ramasubbu Sankararamakrishnan Biophys J. 2016 May 10;110(9):1967-79. doi: 10.1016/j.bpj.2016.03.034.
Contrary to DNA double-helical structures, hydrogen bonds (H-bonds) involving nitrogen as the acceptor are not common in protein structures. We systematically searched N-H…N H-bonds in two different sets of protein structures. Data set I consists of neutron diffraction and ultrahigh-resolution x-ray structures (0.9 Å resolution or better) and the hydrogen atom positions in these structures were determined experimentally. Data set II contains structures determined using x-ray diffraction (resolution ≤ 1.8 Å) and the positions of hydrogen atoms were generated using a computational method. We identified 114 and 14,347 potential N-H…N H-bonds from these two data sets, respectively, and 56-66% of these were of the Ni+1-Hi+1…Ni type, with Ni being the proline backbone nitrogen. To further understand the nature of such unusual contacts, we performed quantum chemical calculations on the model compound N-acetyl-L-proline-N-methylamide (Ace-Pro-NMe) with coordinates taken from the experimentally determined structures. A potential energy profile generated by varying the ψ dihedral angle in Ace-Pro-NMe indicates that the conformation with the N-H…N H-bond is the most stable. An analysis of H-bond-forming proline residues reveals that more than 30% of the proline carbonyl groups are also involved in n → π(*) interactions with the carbonyl carbon of the preceding residue. Natural bond orbital analyses demonstrate that the strength of N-H…N H-bonds is less than half of that observed for a conventional H-bond. This study clearly establishes the H-bonding capability of proline nitrogen and its prevalence in protein structures. We found many proteins with multiple instances of H-bond-forming prolines. With more than 15% of all proline residues participating in N-H…N H-bonds, we suggest a new, to our knowledge, structural role for proline in providing stability to loops and capping regions of secondary structures in proteins.
3. Rotational isomerism about the C alpha-CO bond in proline derivatives. 1H and 13C N.m.r. studies of benzyloxycarbonyl-Pro-N-methylamide and pivaloyl-pro-N-methylamide
R Nagaraj, Y V Venkatachalapathi, P Balaram Int J Pept Protein Res. 1980 Oct;16(4):291-8.
The 270 MHz 1H n.m.r. spectrum of benzyloxycarbonyl-Pro-N-methylamide in CDCl3 is exchange broadened at 293 degrees K. Spectral lines due to two species are frozen out at 253 degrees K and a dynamically averaged spectrum is obtained at 323 degrees K. A selective broadening of the C beta and C gamma resonances in the 13C n.m.r. spectrum is observed at 253 degrees K, with a splitting of the C beta and C gamma resonances into a pair of lines of unequal intensity. A similar broadening of C beta and C gamma peaks is also detected in pivaloyl-Pro-N-methylamide where cis-trans interconversion about the imide bond is precluded by the bulky t-butyl group. The rate process is thus attributed to rotation about the C alpha-CO bond (psi) and a barrier (delta G#) of 14 kcal mol-1 is estimated. 13C n.m.r. data for pivaloyl-Pro-N-methylamide in a number of solvents is presented and the differences in the C beta and C gamma chemical shifts are interpreted in terms of rotational isomerism about the C alpha-CO bond.
