Exploring the Reaction Surface of Cu(I) Transfer from Atx1 to Ccc2a Protein: A Theoretical Study

Abstract In this study, a detailed mechanism for the copper transfer between the yeast Atx1 and Ccc2a (P‐type‐ATPase) is proposed. To explore the potential energy surface (PES) of the reaction pathway, the density functional theory (DFT)‐based B3LYP/6‐31+G** ∪ Lanl2DZ method was used for the active site model. The effect of protein environment on the reaction pathway was unraveled by Our own N‐layered Integrated molecular Orbital and molecular Mechanics (ONIOM model) using B3LYP/6‐31+G** ∪ Lanl2DZ:UFF method. Results obtained from the calculations unveil the formation of kinetically stable 3‐coordinated intermediate IM3(ONIOM). It also provides information on the irreversibility of Cu(I) transfer from Atx1 to Ccc2a domain. The proposed mechanism enables us to understand the rate‐determining step and activation barrier of the transfer, which is 14.15 kcal/mol for active site model and 22.87 kcal/mol for ONIOM model. It is evident from NBO analysis that the interaction between K65‐Atx1 and Cu(I)–S 3 unit is mediated by the water molecule, which is responsible for the stabilization of the 3‐coordinate intermediate (IM3). These results provide a new insight into the Cu(I) transfer mechanism in chaperones.