Macromol. Symp. zyxwvuts 138, zyxwvut 41-25 (1999) zyxwv 41 zy Modelling of Molecular Interactions and Inclusion Phenomena in Substituted P-Cyclodextrin: From Simple Probes to Proteins zyxw S. Miertus, E. Chielhi* zyxwvu a), F. Chiellinia), J. Kona, J. Tomasia), R. Solaroa) International Centre for Science and High Technology of United Nations Industrial Development Organization (ICS UNIDO), Padriciano 99.1-3401 2 Trieste, Italy a) Department of Chemistry and Industrial Chemistry, University of Pisa, via Risorgimento 35, 56126 Pisa, Italy SUMMARY: The ability of P-cyclodextrin (PCD) to form stable complexes with a-interferon was investigated. By using simple molecular mechanics approach interaction energy profiles of simple probes passing the center of PCD ring cavity along the main molecular symmetry axis were evaluated first. A computational study of host-guest inclusion complexes between PCD and L-a-aminoacids and some selected pentapeptides was also carried out and aimed at understanding the nature of the driving forces and mechanism, leading to their formation. Relative complexation energies for the complexes and the solvation Gibbs free energies for single L-a-aminoacids were calculated. Both the aminoacid residue inside the PCD cavity and neighbouring residues were found to contribute to the stabilization of PCD complexes with the side-chain of aminoacids present on the surface of a- interferon. The most appropriate number of host PCD molecules for the encapsulation in the first shell of one a-interferon molecule resulted to be 25. Introduction Interferons are proteins which exhibit antiviral, antitumor and immunomodulating activitiesl). Interferons include fibroblast-produced interferon or a-interferon (IFNa), leukocyte interferon (IFNP) consisting of a family of proteins and immune or y-interferon (IFNy)2). They have found several medical applicationsbut there still is a need to improve their efficacy as drugs3). Encapsulation could be one method to increase their biological activity. Preliminary docking calculations4) on INFa by one molecule of P-cyclodextrin (PCD) have shown that their interaction energy ranges from -58 to -226 kJ mol-l. It appears that cyclodextrins may exert an appreciable stabilizing effect on protein system such as interferon. The cyclic oligosaccharide PCD consists of seven a-D-glucopyranose residues covalently bound by a-1,4-linkages, thus forming a ring-shaped structure with a central cavity of about 0.7 nm diameter. PCD may form inclusion complexes with many guest molecules and z 0 WILEY-VCH Verlag GmbH, D-69469 Weinheim, 1999 CCC 1022- 1360/99/$ 17.50+.50/0