Aromatic control of non-contiguouscispeptidyl-proline bonds mediated by CH…π interactions

HimalKantiGanguly andGautamBasu

Department of Biophysics, Bose Institute, P-1/12 CIT Scheme VIIM, Kolkata 700054.

BACKGROUND

The two dimensional Ramachandran map, spanning φ and ψ, ignores contributions from the third backbone dihedral angleω. This is justified since steric factors restrict the peptide bond to the trans and not the cisconformation. However thecis conformation becomes significant when proline appears in the amino acid sequence. Typically the Xaa-Pro bond shows preference for thecis conformation, especially when Xaa is aromatic (Aro). We show that aromatic residues can stabilize thecisPro conformations even when it is not contiguous to the cispeptidyl-prolyl bond in the sequence.

RESULTS

From NMR studies on a peptide series Pro-Pro-Xaa we show that, mediated by C-H⋅⋅⋅π interaction, an aromatic group following Pro-Pro enhances the stability of Pro-cisPro conformation. Interestingly, the population of Pro-cisPro-His is pH-dependent, modulated by the charged state of the His side chain and its electron availability. From NMR studies on another peptide series Xaa-Pro-Tyr it was found that the degree of stabilization of Xaa-cisPro conformation depends on the nature of Xaa, most pronounced for Pro, Ala, Gly, Arg and Trp, reflecting varying strengths of the CH⋅⋅⋅ interaction. Detailed thermodynamics analysis yielded enthalpy difference between the cis and the trans conformations. Database analysis of protein structures also reflected similar differential bias for Xaa as observed for the series of short peptides.

CONCLUSION

Along with a relative thermodynamic stability scale for Xaa, we have established Xaa-Pro-Aro to be a new sequence motif that can stabilize the Xaa-cisPro conformation. Although the driving force behind the stabilization is local (i, i+2) C-H⋅⋅⋅π interaction, the Xaa-cisPro-Aro conformation is also overrepresented in folded proteins indicating that local C-H⋅⋅⋅π interactions can overwhelm opposing global constraints. Thus, even when a protein displays the Xaa-transPro-Aro conformation, it is quite possible that the Xaa-cisPro-Aro conformation plays a role in stabilizing folding intermediates.

  1. Dasgupta, B. Chakrabarti, P. Basu, G. (2007) Enhanced stability of cis Pro-Pro peptide bond in Pro-Pro-Phe sequence motif. FEBS Lett. 581, 4529-32.
  2. Ganguly, H.K. Majumder, B. Chattopadhyay, S. Chakrabarti, P. Basu, G. (2012) Direct evidence for CH...π interaction mediated stabilization of Pro-cisPro bond in peptides with Pro-Pro-aromatic motifs J. Am. Chem. Soc.134, 5661-9

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