(589f) A Hybrid Molecular Mechanics-Elastic Network Model for Studying Zinc Binding to a Zinc-Finger Protein

It is estimated that nearly half of all proteins require a metal ion as an essential cofactor in the structure and/or function of the molecule. In metalloproteins where the metal acts as a structural element it is not well-understood how the metal ion induces folding and stabilization of the protein. To study such processes requires acknowledging the chemical nature of metal-protein interactions. But a satisfactory description of such chemical interactions requires using computationally expensive, quantum chemical calculations. Here we suggest a way to economize on the quantum chemical calculations by dividing the protein into a metal-binding site that interacts with the rest of the protein (the bulk) that is described within the elastic network framework. Using this approach and the available crystal structure, to within a coupling constant we obtain an effective protein-field on the site particles. Here the value of coupling constant is chosen to reproduce the binding energy distribution of the metal with the site. We use all-atom simulations using classical potentials to obtain the target binding energy distribution, although in principle other metrics or even energy distributions from short all-atom ab initio simulations can be used. We use this approach to study Zn(II) binding to a zinc finger protein. We find that without the effective protein-field, the site (in vacuum) is more stable, suggesting that the solvent and the rest of the protein tend to weaken the binding of the metal ion with the site. We present exploratory calculations of the free energy change in replacing Zn(II) with either Co(II) or Fe(II).