Computational Prediction of Circular Dichroism Spectra and Quantification of Helicity Loss upon Peptide Adsorption on Silica

Circular dichroism (CD) spectroscopy is one of the few experimental techniques sensitive to the structural changes that peptides undergo when they adsorb on inorganic material surfaces, a problem of deep significance in medicine, biotechnology, and materials science. Although the theoretical calculation of the CD spectrum of a molecule in a given conformation can be routinely performed, the inverse problem of extracting atomistic structural details from a measured spectrum is not uniquely determined. Especially complicated is the case of oligopeptides, whose folding/unfolding energy landscapes are often very broad and shallow. This means that the CD spectra measured for either dissolved or adsorbed peptides arise from a multitude of different structures, each present with a probability dictated by their relative free-energy variations, according to Boltzmann statistics. Here we present a modeling method based on replica exchange with solute tempering in combination with metadynamics, which allows us to predict both the helicity loss of a small peptide upon interaction with silica colloids in water and to compute the full CD spectra of the adsorbed and dissolved states, in quantitative agreement with experimental measurements. In our method, the CD ellipticity Co for any given wavelength lambda is calculated as an external collective variable by means of reweighting the biased trajectory obtained using the peptide-SiO2 surface distance and the structural helicity as two independent, internal collective variables. Our results also provide support for the often-employed hypothesis that the Theta intensity at lambda = 222 nm is linearly correlated with the peptides' fractional helicity.