Computational insights into the allosteric behavior of mini proinsulin driven by C peptide mobility

Area of Science:

• Biochemistry
• Molecular Biology
• Biophysics

Background:

• Recombinant insulin production faces challenges in refolding efficiency and bioactivity.
• Mini-proinsulin analogs, featuring a truncated C-peptide, offer a potential solution to enhance insulin manufacturing.
• Optimizing insulin analogs is crucial for developing more effective diabetes treatments.

Purpose of the Study:

• To evaluate the design and receptor binding dynamics of mini-proinsulin analogs.
• To optimize recombinant insulin production using engineered mini-proinsulin analogs in E. coli.
• To compare the binding characteristics of mini-proinsulin analogs with native insulin.

Main Methods:

• Engineered mini-proinsulin analogs by replacing the 33-residue C-peptide with a pentapeptide.
• Predicted three-dimensional structures using AlphaFold.
• Performed molecular docking and Normal Mode Analyses (GNM and ANM) to assess receptor binding dynamics.

Main Results:

• Mini-proinsulin analogs structurally resemble native insulin.
• Analog receptor binding dynamics are similar to native insulin, despite distinct interaction pathways.
• C-peptide mobility appears to influence the allosteric behavior during receptor interaction.

Conclusions:

• Mini-proinsulin analogs demonstrate potential for efficient recombinant insulin production.
• The structural and dynamic properties of these analogs support their bioactivity.
• Further research into C-peptide mobility could lead to improved insulin analog design.