Insights into the Thermally Activated Cyclization Mechanism in a Linear Phenylalanine-Alanine Dipeptide

Abstract

Dipeptides, the prototype peptides, exist in both linear ( l -) and cyclo ( c -) structures. Since the first mass spectrometry experiments, it has been observed that some l -structures may turn into the cyclo ones, likely via a temperature-induced process. In this work, combining several different experimental techniques (mass spectrometry, infrared and Raman spectroscopy, and thermogravimetric analysis) with tight-binding and ab initio simulations, we provide evidence that, in the case of l -phenylalanyl- l -alanine, an irreversible cyclization mechanism, catalyzed by water and driven by temperature, occurs in the condensed phase. This process can be considered as a very efficient strategy to improve dipeptide stability by turning the comparatively fragile linear structure into the robust and more stable cyclic one. This mechanism may have played a role in prebiotic chemistry and can be further exploited in the preparation of nanomaterials and drugs.

Electron and ion spectroscopy of the cyclo-alanine–alanine dipeptide

“…This is probably due to the thermal lability of most of these biomolecules which can undergo structural changes during the desorption, particularly in linear dipeptides. 13,20–24…”

“…This is probably due to the thermal lability of most of these biomolecules which can undergo structural changes during the desorption, particularly in linear dipeptides. 13,[20][21][22][23][24] Nevertheless, the driving force for the investigation of dipeptides spans from the need to answer fundamental questions concerning the origin of life 19,25 and the biological activities of larger peptides and proteins, 26 to their exploitation in therapeutic 27 and technological applications. [28][29][30] Cyclo-alanine-alanine (cAA) is one of the simplest cyclo dipeptides.…”

Fragmentation and charge transfer in cyclic dipeptides with an aromatic side chain induced by VUV radiation

“…At these temperatures no degradation of the samples occurs. This has been established according to the procedure presented in [25], which involves the measurement of the optical spectra of the pristine sample and of the sample left in the crucible after heating. An example of the procedure is reported in the supplementary information (SI).…”

“…The structure of this dipeptide (figure 1) is made by a central DKP ring and a phenyl side chain connected through a flexible -CH 2 -bridge. The main features of the sum of all PEPICO spectra in figure 3(a) have been assigned in table 1 according to the previous literature [25,[46][47][48]. The parent cation is clearly visible at m/z 204; the C 7 H 7 ion (m/z 91) and its complementary fragment [C 4 H 5 N 2 O 2 ] + (m/z 113) may be attributed to the benzyl residual or its loss from the parent ion; the [C 3 H 5 N 2 O] + (m/z 85) may result from a further CO loss from m/z 113 with two bond breaks and the opening of the ring; the feature at m/z 65 has been assigned to the loss of acetylene C 2 H 2 from the C 7 H 7 + producing the C 5 H 5 ion; fragments at m/z 43 and 30 may be tentatively assigned to further fragment-…”

Photoelectron–photoion(s) coincidence studies of molecules of biological interest

“…This is probably due to the thermal lability of most of these biomolecules which can undergo structural changes during the desorption, particularly in linear dipeptides. 63,70 The driving force for the investigation of dipeptides spans from the need to answer questions concerning the origin of life and the biological activities of larger peptides and proteins, to their exploitation in therapeutic and technological applications.…”