Computational IR Spectroscopy of Insulin Dimer Structure and Conformational Heterogeneity.

Area of Science:

• Biophysics
• Computational Chemistry
• Structural Biology

Background:

• Insulin dimer structure and dynamics are crucial for its function.
• Understanding conformational changes is key to interpreting experimental data.

Purpose of the Study:

• Investigate insulin dimer structure and dynamics using computational methods.
• Develop tools for experimental resolution of conformational variations via IR spectroscopy.

Main Methods:

• Atomistic molecular dynamics simulations.
• Markov state modeling (MSM) to capture conformational landscapes.
• Infrared (IR) spectral simulations of labeled insulin.

Main Results:

• Identified two dominant insulin dimer conformations: native and a rotated twisted state.
• Twisted state involves altered C-terminal B chain contacts and side-chain packing.
• MSM predicts interconversion on a 14 μs timescale.
• Amide I spectroscopy simulations show native and twisted states are distinguishable with specific isotopic labeling.

Conclusions:

• Computational models reveal key insulin dimer conformations and dynamics.
• IR spectroscopy, particularly amide I, offers a method to experimentally probe these states.
• Provides interpretive framework for advanced IR kinetic studies of insulin.