D130A variant on Parkinson 22-related CHCHD2 is predicted to have decreased protein movement

Abstract

Parkinson's disease is the second most common neurodegenerative disease which is caused by a lack of dopamine in the brain. Parkinson 22 is a form of Parkinson's disease caused by variations in the coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) protein. This study investigates an aspartic acid-to-alanine swap on amino acid position 130 (D130A) of the CHCHD2 protein. We have employed protein modeling, conservation analysis, and molecular dynamics simulations to gain an understanding of the effects of the D130A variant on CHCHD2 protein structure and movement.

Figure 1. Characterization of D130A

A) Analyzed pathogenicity using in silico predictors SIFT, PolyPhen-2, CADD Tools, REVEL, and Meta LR. All scores were normalized for comparison. D130A variant (purple) is ranked as more likely pathogenic than the known pathogenic variants (blue) of CHCHD2 (Ng & Henikoff, 2001; Adzhubei et al., 2010; Rentzsch et al., 2021; Ioannidis et al., 2016; Willer et al., 2010). B) Amino acid conservation analysis of the 150 species (left). YASARA homology modeling of CHCHD2 protein (right) (Ashkenazy et al, 2016)(Land et al. 2016). C) The carbon alpha root-mean-squared fluctuation (RMSF) of each amino acid throughout the 20 ns simulation. D) 20 nanoseconds (ns) of molecular dynamic simulation for the CHCHD2 protein shows the root-mean-squared deviation (RMSD) of the average carbon alpha from the initial structure to each time point of the simulation.