Abstract:
Molybdenum cofactor deficiency (MoCD) is a severe inborn disease first described by Duran
and coworkers in 1978 as defective metabolism followed by loss of activities of all molybdenum
dependent enzymes. It is an autosomal recessive disease caused by defect in any of the genes
involved in the conserved pathway of molybdenum cofactor (MoCo) synthesis. The genes
involved in MoCo biosynthesis are Molybdenum Cofactor Synthesis 1 (MOCS1), Molybdenum
Cofactor Synthesis 2 (MOCS2), Molybdenum Cofactor Synthesis 3 (MOCS3) and Gephyrin
(GPHN). MOCS1 proteins (MOCS1A and MOCS1B) are involved in the formation of cyclic
pyranopterin monophosphate (cPMP), first intermediate in MoCo biosynthesis, from Guanosine
Tri-phosphate (GTP). If this first intermediate cPMP is not synthesized, leads to MoCD type-A
disease owing to mutations in MOCS1 gene. Computational analysis was performed on the first
biosynthetic step of molybdenum cofactor biosynthesis, formation of cPMP, using normal
MOCS proteins as well as mutated MOCS1 proteins. Protein-ligand interaction studies,
molecular docking and molecular dynamics (MD) simulations were performed to investigate the
reasons behind MoCD type-A. Comparison between the results obtained for the formation of
cPMP using the normal and mutated pathways helped to understand the different protein-ligand
interactions leading to MoCD type-A. Binding affinities are also affected due to the mutations
in the MOCS1 proteins which develop newly unfavorable and strong interactions that disturb the
normal synthesis of cPMP. Potential energy studies also fortified the results and suggested the
after mutation, energy required to make the reaction possible becomes greater making the
formation of intermediate difficult or defective, leading to MoCD type-A disease.
