The secondary structure of the loop IIId domain in the RNA of hepatitis C virus (HCV) is well-conserved among different genotypes of HCV, which suggests that the nucleocapsid proteins may interact with the genome RNA through this loop structure. Using infrared spectroscopy, we monitored structural changes occurring in HCV core protein and loop IIId upon formation of nucleocapsid-like particles (NLPs). The protein secondary structure of these particles involves beta-sheet enrichment in relation to its protein monomer. The phosphodiester backbone vibrations of loop IIId reflect the predominant C3'-endo conformation of the riboses involved in the RNA A-form and reveal the packaging-imposed transition of the said RNA segments toward single-stranded structure within the NLPs. Intermolecular protein-nucleic acid contacts in these particles involve RNA phosphate groups and positively charged amino acid residues such as arginine and lysine. Two-dimensional correlation spectroscopic analysis of the spectra measured in the course of deuteration shows synchronous cross-peaks correlating two bands assigned to guanine and arginine side chain, which is consistent with the presence of guanine-arginine interactions in these NLPs. This is also supported by the kinetically favored formation of NLPs having HCV core protein and guanine-enriched synthetic oligonucleotides. We also found that these NPLs are fully permeable to water molecules.