Molecular dynamics perspective on the protein thermal stability: a case study using SAICAR synthetase

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• SAICAR synthetase catalyzes a key step in purine biosynthesis.
• Previous research focused on structural aspects of enzyme thermostability.
• Understanding dynamic differences is crucial for enzyme function across temperature ranges.

Purpose of the Study:

• To investigate the dynamic properties of SAICAR synthetases from mesophilic, thermophilic, and hyperthermophilic organisms.
• To identify molecular determinants of enzyme stability across different temperature optima.
• To compare dynamic behaviors at various temperatures using molecular dynamics simulations.

Main Methods:

• Molecular dynamics simulations of five functional SAICAR synthetase dimers (mesophilic, thermophilic, hyperthermophilic).
• Simulations conducted at 300 K, 363 K, and 333 K (for thermophilic).
• Analysis of root-mean-square deviations, root-mean-square fluctuations, surface accessibility, radius of gyration, mean square displacements, and hydrogen bonds.

Main Results:

• Mesophilic SAICAR synthetases exhibit instability at 363 K, evidenced by increased short-lived interactions and loss of long-lived contacts.
• Hyperthermophilic and thermophilic enzymes demonstrate reduced flexibility across all simulated temperatures.
• Significant changes in long-distance networks and salt-bridge accessibility were observed in mesophiles at elevated temperatures.

Conclusions:

• Dynamic properties differentiate SAICAR synthetases based on their optimal growth temperatures.
• Mesophilic enzymes are less stable at high temperatures due to altered interaction dynamics.
• Hyperthermophilic enzymes possess inherent flexibility and stability mechanisms suited for extreme environments.