Solvents play an important role in protein folding, protein-protein associations, stability, and specificity of recognition as in the case of antibody-antigen interactions through hydrogen bonds. One of the underappreciated features of protein-associated waters is that it weakens inter- and intra-molecular interactions by modulating electrostatic interactions and influencing conformational changes. Such observations demonstrate the direct relationship between macroscopic solvent effects on protein-protein interactions and atom-scale solvent-protein interactions. Although crystallographic solvents do explain some aspects of solvent-mediated interactions, molecular simulation allows the study of the dynamic role of solvents. Thus, analysis of conformations from molecular simulations are employed to understand the role of solvent on the inherent polyspecificity of a Lewis Y reactive germline gene relative to its expanded hybridomas and a humanized anti-Lewis Y antibody. Our analysis reveals that solvent mediates critical contacts through charged residues to facilitate cross-reactivity to carbohydrate antigens, but also increases the flexibility of some anti-Lewis Y antibodies concomitant with mutations (amino acid substitutions) to the germline antibody. Such flexibility might better allow for recognition and binding of internal structures of extended carbohydrate structures on tumor cells.