A molecular dynamics approach on the Y393C variant of protein disulfide isomerase A1

Human protein disulfide isomerase A1 (PDIA1) shows both catalytic (i.e., oxidoreductase) and non‐catalytic (i.e., chaperone) activities and plays a crucial role in the oxidative folding of proteins within the endoplasmic reticulum. PDIA1 dysregulation is a common trait in numerous pathophysiological conditions, including neurodegenerative disorders and cancerous diseases. The 1178A>G mutation of the human PDIA1‐encoding gene is a non‐synonymous single nucleotide polymorphism detected in patients with Cole‐Carpenter syndrome type 1 (CSS1), a particularly rare bone disease. In vitro studies showed that the encoded variant (PDIA1 Y393C) exhibits limited oxidoreductase activity. To gain knowledge on the structure–function relationship, we undertook a molecular dynamics (MD) approach to examine the structural stability of PDIA1 Y393C. Results showed that significant conformational changes are the structural consequence of the amino acid substitution Tyr>Cys at position 393 of the PDIA1 protein. This structure‐based study provides further knowledge about the molecular origin of CCS1. Human protein disulfide isomerase A1 (PDIA1) plays a crucial role in protein oxidative folding. The 1178A>G mutation of the human PDIA1‐encoding gene is a non‐synonymous SNP detected in patients with Cole‐Carpenter syndrome type 1. Here, we undertook a molecular dynamics approach to examine the structural stability of PDIA1 Y393C, the encoded variant. Results showed that significant conformational changes are the structural consequence of the amino acid substitution Tyr>Cys at position 393 of the PDIA1 protein.