Disorder Mediated Oligomerization of DISC1 Proteins Revealed by Coarse-Grained Molecular Dynamics Simulations

Abstract

Disrupted-in-schizophrenia-1 (DISC1) is a scaffold protein of significant importance for neuro-development and a prominent candidate protein in the etiology of mental disorders. In this work, we investigate the role of conformational heterogeneity and local structural disorder in the oligomerization pathway of the full-length DISC1 and of two truncation variants. Through extensive coarse-grained molecular dynamics simulations with a predictive energy landscape-based model, we shed light on the interplay of local and global disorder which lead to different oligomerization pathways. We found that both global conformational heterogeneity and local structural disorder play an important role in shaping distinct oligomerization trends of DISC1. This study also sheds light on the differences in oligomerization pathways of the full-length protein compared to the truncated variants produced by a chromosomal translocation associated with schizophrenia. We report that oligomerization of full-length DISC1 sequence works in a nonadditive manner with respect to truncated fragments that do not mirror the conformational landscape or binding affinities of the full-length unit.