Simulation of conformational changes in 2 Zn insulin

Area of Science:

• Biochemistry
• Structural Biology
• Computational Chemistry

Background:

• Insulin exists in various aggregated states, including monomers and dimers, influencing its biological activity.
• The 2 Zn crystal structure provides a basis for understanding insulin's quaternary structure.
• Previous studies proposed mechanisms for conformational coupling within insulin molecules.

Purpose of the Study:

• To investigate the conformational dynamics of insulin monomers, dimers, and higher aggregates using computational methods.
• To determine the preferred conformation of insulin in the absence of crystal packing forces.
• To re-evaluate the role of dimer formation in the observed asymmetry of the 2 Zn insulin crystal structure.

Main Methods:

• Convergent energy minimization of isolated insulin monomers, dimers, and aggregates.
• Utilized Cartesian coordinates and a comprehensive force field including all hydrogen atoms.
• Compared computational results with observed structural differences in the 2 Zn crystal.

Main Results:

• Energy minimization induced significant conformational changes in insulin monomers, dimers, and aggregates.
• The calculated conformational changes align well with experimental observations of monomer structures in the 2 Zn crystal.
• Results support a previously proposed mechanism for coupling deformations across different molecular regions.
• Simulations suggest insulin favors a monomer-like conformation when crystal packing forces are absent.

Conclusions:

• Insulin monomers exhibit substantial conformational flexibility, influenced by energy minimization.
• Crystal packing forces play a crucial role in stabilizing higher-order insulin structures.
• Dimer formation is unlikely to be the primary cause of asymmetry observed in the 2 Zn insulin crystal.