Dynamic simulations of oxygen binding to myoglobin

Area of Science:

• Biophysics
• Computational Chemistry
• Protein Dynamics

Background:

• Myoglobin is crucial for oxygen transport and storage in muscles.
• Understanding ligand diffusion within myoglobin is key to its function.
• Previous studies have explored heme pocket interactions, but dynamic pathways remain complex.

Purpose of the Study:

• To simulate and analyze the dynamic process of dioxygen entry and exit from the myoglobin heme pocket.
• To determine the energetic and entropic contributions to the gas transport barrier.
• To evaluate the applicability of transition state theory to this biological process.

Main Methods:

• Utilized molecular dynamics simulations to model dioxygen movement within myoglobin.
• Employed umbrella sampling with constraining potentials to map the potential of mean force.
• Defined a reaction coordinate based on the ligand's distance from a protein-defined dividing plane.
• Generated reactive trajectories to analyze the dynamics at the transition state.

Main Results:

• Identified a primary pathway for dioxygen passage between distal histidine (E7) and valine (E11).
• Calculated a free energy barrier of approximately 7 kcal/mol for ligand exit from the heme pocket.
• Demonstrated that entropic factors play a dominant role in the kinetic barrier.
• Observed a low recrossing rate of reactive trajectories, supporting transition state theory.

Conclusions:

• Entropy significantly influences the kinetics of gas exchange in myoglobin.
• Transition state theory provides a reasonable approximation for modeling dioxygen transport through the heme pocket.
• The identified pathway and energetic landscape offer insights into myoglobin's oxygen binding and release mechanisms.