Computational studies of ligand diffusion in globins: I. Leghemoglobin

Area of Science:

• Computational biophysics
• Protein dynamics
• Ligand diffusion

Background:

• Understanding ligand diffusion through protein matrices is crucial for various biological processes.
• Previous studies have explored ligand-protein interactions, but detailed pathways remain elusive.
• Lupine leghemoglobin and myoglobin serve as model systems for studying heme protein dynamics.

Purpose of the Study:

• To computationally investigate the thermally assisted diffusion of carbon monoxide (CO) within lupine leghemoglobin.
• To elucidate the molecular mechanisms governing CO diffusion pathways and rates.
• To compare diffusion dynamics between leghemoglobin and myoglobin.

Main Methods:

• Utilized a variant of the time-dependent Hartree approximation, termed Locally Enhanced Sampling (LES).
• LES enhances ligand trajectory searches by using a single protein trajectory.
• Calculated diffusion pathways and compared diffusion rates qualitatively between leghemoglobin and myoglobin.

Main Results:

• Diffusion of CO in leghemoglobin is significantly faster than in myoglobin, aligning with experimental data.
• Identified a key gate-opening mechanism in leghemoglobin involving fluctuations between the B/C and G helices.
• The primary fluctuation involves a rigid shift of the C helix relative to the G helix, a path not seen in myoglobin.

Conclusions:

• The enhanced diffusion in leghemoglobin is attributed to the absence of the D helix and a more flexible CE loop.
• These structural differences facilitate a distinct gate-opening mechanism compared to myoglobin.
• Findings support experimental evidence highlighting the CE loop's importance in leghemoglobin kinetics.