The interaction of l-tryptophan (Trp) with silver colloids was investigated at between pH values of 6.11 and 10.6 of the sol. The measurements of surface-enhanced Raman bands of Trp in the colloidal solution indicate the evolution of interaction between the metal particles and the molecules with increasing pH values for the sol. The experimental observations were explained using the estimated atomic charge distribution in the zwitterionic and anionic forms of the residue, obtained by density functional theory calculations. The variation in the ratio of the spectral intensities of the Fermi resonance bands with the pH reflects the effect of the colloidal environment on Trp. The results obtained can be used as a marker for describing the nature of the interaction of silver colloids with the specific terminus of the residue, at varying pH environments. Copyright © 2012 John Wiley & Sons, Ltd.