Abstract
Human mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMG-CoA synthase, mHS) synthase is a key enzyme in ketogenesis and is located mainly in the liver, but also in the colon, skeletal muscle, heart, pancreas, and testes. It is an inner mitochondrial membrane-associated protein. Mutations in the HMGCS2 gene, which encodes this enzyme, lead to "mHS deficiency," a rare, autosomal recessive, inherited metabolic disorder. To date, about 100 patients with this disorder have been described. The disorder usually appears during the first year of life, often after a period of starvation or an intercurrent illness. A total of 77 different DNA mutations has been described that are considered responsible for mHS deficiency, although the mechanisms leading to loss of function are not fully understood. To study how the different missense variants affect the enzymatic activity of the protein on an atomic scale, we used molecular dynamics computational simulation techniques for variants whose activity could be measured "in vitro." The study included a total of 46 molecular dynamics trajectories of enzyme-substrate/product interaction simulations, each 500 ns long (23 microseconds total). Currently, the atomic and biophysical effects of the mHS variants on their catalyzed reactions have not been studied in detail experimentally. To our knowledge, molecular dynamics simulations are one of the most promising tools for understanding the molecular basis of the phenotypic consequences of these variants. In the present work, molecular dynamics simulations reliably reproduce most experimental enzyme activity measurements, supporting their future application to the study of new mHS mutations.