The trisaccharide 3,6-di-O-(a-D-mannopyranosyl)-D-mannose, which is present in all asparagine-linked carbohydrates, was previously shown by titrn. micro-calorimetry to bind to the lectin Con A (ConA) with nearly -6 kcal mol-1 greater enthalpy change and 60-fold higher affinity than methyl-a-D-mannopyranoside (Mandal, D. K., Kishore, N., and Brewer, C. F. (1994) Biochem. 33, 1149-1156). Similar studies of the binding of a series of monodeoxy derivs. of the a(1-3) residue of the trimannoside showed that this arm was required for high affinity binding (Mandal, D. K., Bhattacharyya, L., Koenig, S. H., Brown, R. D., III, Oscarson, S., and Brewer, C. F. (1994) Biochem. 33, 1157-1162). In the present paper, a series of monodeoxy derivs. of the a(1-6) arm and \"core\" Man residue of the trimannoside as well as dideoxy and trideoxy analogs were synthesized. Isothermal titrn. microcalorimetry expts. establish that the 3-, 4-, and 6-hydroxyl groups of the a(1-6)Man residue of the trimannoside binds to the lectin, along with the 2- and 4-hydroxyl groups of the core Man residue and the 3- and 4-hydroxyl groups of the a(1-3)Man residue. Dideoxy analogs and trideoxy analogs showed losses of affinities and enthalpy values consistent with losses in binding of specific hydroxyl groups of the trimannoside. The free energy and enthalpy contributions to binding of individual hydroxyl groups of the trimannoside detd. from the corresponding monodeoxy analogs are obsd. to be nonlinear, indicating differential contributions of the solvent and protein to the thermodn. of binding of the analogs. The thermodn. soln. data agree well with the recent x-ray crystal structure of ConA complexed with the trimannoside (Naismith, J. H., and Field, R. A. (1996) J. Biol. Chem. 271, 972-976). [on SciFinder (R)]