Computational analysis of missense mutations causing Snyder-Robinson syndrome

Area of Science:

• Biochemistry
• Genetics
• Computational Biology

Background:

• Snyder-Robinson syndrome is a genetic disorder caused by missense mutations in the spermine synthase (SMS) gene.
• SMS encodes a protein crucial for spermine production, and its dysfunction leads to disease.
• Understanding the molecular impact of specific mutations is key to comprehending disease mechanisms.

Purpose of the Study:

• To investigate the in silico molecular effects of three identified missense mutations (p.G56S, p.V132G, p.I150T) in the SMS gene.
• To analyze how these mutations affect SMS protein stability, flexibility, and interactions.
• To correlate structural changes with the observed clinical manifestations of Snyder-Robinson syndrome.

Main Methods:

• In silico analysis including single-point energy calculations.
• Molecular dynamics simulations to assess protein dynamics and stability.
• pKa calculations to predict changes in residue protonation states and their impact on substrate binding.

Main Results:

• The p.I150T mutation alters pKa values of residues interacting with the S-methyl-5'-thioadenosine (MTA) substrate, decreases C-terminal domain stability, and affects the MTA binding site.
• The p.G56S mutation significantly reduces monomer affinity for dimerization, which is essential for SMS activity.
• The p.V132G mutation affects monomer and dimer stability but is located away from the active site.

Conclusions:

• The p.I150T and p.G56S mutations provide distinct molecular mechanisms for Snyder-Robinson syndrome.
• p.I150T directly impacts substrate interaction and stability near the active site.
• p.G56S disrupts the essential dimerization process, highlighting the importance of protein quaternary structure in disease pathogenesis.