Molecular insights into mutation-induced conformational changes in Acetyl CoA Carboxylase for improved activity

Acetyl-CoA carboxylase (ACCase) is crucial for fatty acid biosynthesis and has potential applications in lipid accumulation and advanced biofuel production. Mutations like S659A and S1157A in Saccharomyces cerevisiae ACCase remove the Snf1-regulation sites, resulting in increased enzyme activity with positive effects on the fatty acid pathway. However, the molecular-level understanding of these mutations on ACCase activity remains unexplored. Here, molecular dynamics simulation was conducted to investigate the mutations-induced conformational changes in S. cerevisiae ACCase. The wild-type ACCase was observed to have significant deviation in structure compared to mutant. Additionally, fluctuation of residues associated with biotin binding and Snf1-recognition were reduced in mutant compared to wild-type. Furthermore, the wild-type demonstrated opening motions of the domains, whereas the mutant showed closing movement. The mutation-induced conformational changes were analysed using network parameters, i.e., cliques/communities. The mutant showed an increase in sizes of several communities in AC3-AC4-AC5 domains leading to rigidification. Also, a new community was added in AC1-BT in the mutant, which suggested a substantial shift in the protein conformation. Thus, this study provides a theoretical understanding of the increased activity of ACCase due to two mutations, which can pave the path for enzyme engineering towards improved fatty acid-based fuel and chemical production.