Structural prediction of the β-domain of metallothionein-3 by molecular dynamics simulation

The β-domain of metallothionein-3 (MT3) has been reported to be crucial to the neuron growth inhibitory bioactivity. Little detailed three-dimensional structural information is available to present a reliable basis for elucidation on structure-property-function relationships of this unique protein by experimental techniques. So, molecular dynamics simulation is adopted to study the structure of β-domain of MT3. In this article, a 3D structural model of β-domain of MT3 was generated. The molecular simulations provide detailed protein structural information of MT3. As compared with MT2, we found a characteristic conformation formed in the fragment (residue 1-13) at the N-terminus of MT3 owing to the constraint induced by ⁵TCPCP⁹, in which Pro7 and Pro9 residues are on the same side of the protein, both facing outward and the two 5-member rings of prolines are arranged almost in parallel, while Thr5 is on the opposite side. Thr5 in MT3 is also found to make the first four residues relatively far from the fragment (residue 23-26) as compared with MT2. The simulated structure of β-domain of MT3 is looser than that of MT2. The higher energy of MT3 than that of MT2 calculated supports these conclusions. Simulation on the four isomer arising from the cis- or trans-configuration of ⁶CPCP⁹ show that the trans-/trans-isomer is energetic favorable. The partially unfolding structure of β-domain of MT3 is also simulated and the results show the influence of ⁶CPCP⁹ sequence on the correct folding of this domain. The correlations between the bioactivity of MT3 and the simulated structure as well as the folding of β-domain of MT3 are discussed based on our simulation and previous results.