Tidying up the conformational ensemble of a disordered peptide by computational prediction of spectroscopic fingerprints

In this work we demonstrate that oligopeptides lacking a clear propensity for ordered secondary-structure motifs are not randomly, but only conditionally disordered. This means that their conformational landscape, or phase-space, can be well represented by a basis-set of conformers including about 10 to 100 structures. The implications of this finding have profound consequences both for the interpretation of experimental electronic and vibrational spectral features of peptides in solution and for the theoretical prediction of these features using accurate and computationally expensive techniques. These concepts are elaborated for and applied to a dodecapeptide, whose Circular Dichroism, Infrared, Raman and Raman-Optical-Activity spectroscopic fingerprint is measured and theoretically predicted by means of enhanced-sampling Molecular Dynamics coupled with Quantum Mechanical calculations. The here-derived methods and conclusions are expected to fundamentally impact the rationalization of so-far elusive structure-function relationships for disordered peptides and proteins in biochemistry and biomaterials science.