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Molecular Basis for the Cu²⁺ Binding-Induced Destabilization of ß2-Microglobulin Revealed by Molecular Dynamics Simulation

Accelrys Inc., San Diego, California 92121

Correspondence: Address reprint requests to Nan-Jie Deng, E-mail: ndeng{at}accelrys.com.

According to experimental data, binding of the Cu²⁺ ions destabilizes the native state of ß2-microglobulin (ß2m). The partial unfolding of the protein was generally considered an early step toward fibril formation in dialysis-related amyloidosis. Recent NMR studies have suggested that the destabilization of the protein might be achieved through increased flexibility upon Cu²⁺ binding. However, the molecular mechanism of destabilization due to Cu²⁺, its role in amyloid formation, and the relative contributions of different potential copper-binding sites remain unclear. To elucidate the effect of ion ligation at atomic detail, a series of molecular dynamics simulations were carried out on apo- and Cu²⁺-ß2m systems in explicit aqueous solutions, with varying numbers of bound ions. Simulations at elevated temperatures (360 K) provide detailed pictures for the process of Cu²⁺-binding-induced destabilization of the native structure at the nanosecond timescale, which are in agreement with experiments. Conformational transitions toward partially unfolded states were observed in protein solutions containing bound copper ions at His-31 and His-51, which is marked by an increase in the protein vibrational entropy, with TS(vibr) ranging from 30 to 69 kcal/mol. The binding of Cu²⁺ perturbs the secondary structure and the hydrogen bonding pattern disrupts the native hydrophobic contacts in the neighboring segments, which include the ß-strand D2 and part of the ß-strand E, B, and C and results in greater exposure of the D-E loop and the B-C loop to the water environment. Analysis of the MD trajectories suggests that the changes in the hydrophobic environment near the copper-binding sites lower the barrier of conformational transition and stabilize the more disordered conformation. The results also indicate that the binding of Cu²⁺ at His-13 has little effect on the conformational stability, whereas the copper-binding site His-31, and to a lesser extent His-51, are primarily responsible for the observed changes in the protein conformation and dynamics.

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