Rate of Insulin Dimer Dissociation: Interplay between Memory Effects and Higher Dimensionality

Area of Science:

• Biophysics
• Computational Chemistry
• Molecular Dynamics

Background:

• Insulin exists as a dimer in aqueous solution, and its dissociation into monomers is crucial for biological function.
• Understanding the kinetics of insulin dimer dissociation is essential for drug development and understanding diabetes.

Purpose of the Study:

• To calculate the rate of insulin dimer dissociation in water.
• To elucidate the factors determining this complex reaction rate.
• To investigate the influence of dimensionality and memory effects on the reaction rate constant.

Main Methods:

• Advanced sampling techniques to obtain the reaction free energy surface.
• Construction of an orthogonal 2D reaction energy surface using reaction coordinates R and Q.
• Application of non-Markovian multidimensional rate theory and other theoretical approaches.
• Calculation of reaction frequencies and frictions using time correlation function formalism.
• Analysis of molecular dynamics simulation trajectories.

Main Results:

• The free energy landscape for insulin dimer dissociation is rugged, featuring multiple maxima and minima.
• The calculated rate of insulin dimer dissociation is 0.4 μs⁻¹.
• Dimensionality and memory effects were found to have opposing influences on the reaction rate constant.

Conclusions:

• The study provides a detailed kinetic analysis of insulin dimer dissociation.
• Insights into the complex interplay of factors governing the reaction rate were gained.
• The findings contribute to a deeper understanding of protein dynamics and biomolecular interactions.