Alcohol binding to the odorant binding protein LUSH: multiple factors affecting binding affinities

Area of Science:

• Computational chemistry
• Structural biology
• Biophysics

Background:

• The odorant binding protein LUSH from Drosophila melanogaster binds ethanol at physiologically relevant concentrations.
• High-resolution structural data exists for LUSH-alcohol complexes, revealing critical hydrogen-bonding interactions for ethanol binding.

Purpose of the Study:

• To investigate alcohol binding to the LUSH protein using Density Functional Theory (DFT) calculations.
• To compare the performance of different DFT models (B3LYP and M05-2X) in predicting binding affinities.
• To identify key factors contributing to alcohol binding affinity.

Main Methods:

• DFT calculations were performed on truncated models of LUSH-alcohol complexes.
• Both gas-phase and continuum solvation model calculations were employed.
• The study evaluated the B3LYP and M05-2X DFT models.

Main Results:

• The B3LYP DFT model failed to reproduce the experimentally observed trend of increasing binding affinity with alcohol alkyl chain length.
• The M05-2X DFT model successfully reproduced this trend, indicating its suitability for such calculations.
• Key binding factors include hydrogen bonding with Thr57 and Ser52, desolvation effects, and noncovalent interactions along the alcohol's alkyl chain.

Conclusions:

• The M05-2X DFT model shows significant potential for accurately calculating protein-substrate interactions, especially those involving noncovalent forces.
• Understanding these interactions is crucial for predicting binding affinities in biological systems.