When Additive Molecular Dynamics Fails: Quantum Effects In Calcium-Dependent Lectin/Carbohydrate Complex

The developments of additive carbohydrate force fields increased the reliability of molecular dynamics simulations (MD) of protein-carbohydrate complexes. The presence of bridging Ca2+ ions can, however, pose problems for structural and energetic description due to quantum effects, such as charge transfer. To overcome this limitation, we have developed Ca2+ parameters with effective electronic polarisation for use with additive force fields and applied them to a calcium-dependent lectin/carbohydrate complex. Such a treatment improved the structural description of the binding site (Ca2+ċċċCa2+ distance matching that of the crystal structure) but failed to reproduce the pattern of protein/carbohydrate interactions and the location of specific bridging water molecules. This system thus necessitated the use of polarizable force fields. Coupled with quantum mechanical/molecular mechanical (QM/MM) calculations, we were able to describe the polarization phenomena of the Ca2+ ions, protein carboxylate side chains, carbohydrate hydroxyls and specific water molecules in the active site which together define the structure and energetics of the complex. In summary, we utilized new Ca2+ parameters and advanced computational techniques (polarizable MD, QM/MM calculations) on the crystallographic structure to gain atomistic and energetic understanding of the Ca2+-dependent lectin/carbohydrate complex.