Bioinformatics and Molecular Dynamics Studies on the Human DISC1 in Complex with the Ndel1.

In this study we analyzed the sequence and structure of the human DISC1-Ndel1 complex using bioinformatics tools and molecular dynamics simulation studies. Multiple sequence alignment between the homologue protein sequences in primates shows that corresponding positions of residues in Ndel1 are highly conserved, while the DISC1 has variable conservation lines demonstrating its tolerability against various mutations during evolutionary time scale. In comparison with the mouse variant, structural analysis has shown that the evolutionary inserted charged residues in the human DISC1 (E 8 3 7 -R 8 3 8 ) can establish intra-chain electrostatic interactions with the K 8 1 9 -E 8 2 0 dipeptide that may result in more stability of the DISC1 chain. According to MD simulation studies, the compactness for the human variant of the DISC1-Ndel1 is considerably lower than that of the mouse variant. Analysis of structural fluctuation shows that a fragment at the N-terminus side of the human DISC1 has more residual fluctuation. However, the Ndel1 chain of the human variant has globally more flexibility compared with the mouse variant. Considering the identical amino acid sequence of the Ndel1 chains of human and mouse, it concluded that there is a competition between the inter-chain and intra-chain electrostatic interaction in the human DISC1 that directs the complex to weaker inter-chain interactions with the expense of strengthening the intra-chain stabilizing interaction in complex. Human DISC1-Ndel1complex has important neurobiological roles. The interacting fragment of DISC1 shows a degree of variability within primates, and that of Ndel1 is highly conserved. Occurrence of more charged residues in human DISC1 leads to strengthening the intra-chain electrostatics interaction. [ABSTRACT FROM AUTHOR]