Quantifying Induced Dipole Effects in Small Molecule Permeation in a Model Phospholipid Bilayer

Area of Science:

• Biophysics
• Computational Chemistry
• Membrane Biology

Background:

• Cell membranes act as semipermeable barriers, controlling substance transport.
• The lipid bilayer exhibits a dielectric gradient due to amphiphilic lipids.
• This gradient impacts small molecule permeation and membrane protein function.

Purpose of the Study:

• To investigate the influence of the electronic environment on molecular permeation across cell membranes.
• To compare the accuracy of polarizable versus nonpolarizable force fields in simulating these effects.
• To quantify the impact of dielectric gradient on permeation free energy surfaces.

Main Methods:

• Employed polarizable molecular dynamics (MD) simulations using the Drude force field (FF).
• Simulated eight amino acid side chain analogs within a lipid bilayer.
• Utilized unbiased and umbrella sampling techniques.
• Compared results with simulations using the nonpolarizable CHARMM36 FF.

Main Results:

• Evaluated molecular dipole moments, showing variations based on membrane localization.
• Analyzed free energy surfaces of permeation for different amino acid analogs.
• Demonstrated differences in permeation behavior between polarizable and nonpolarizable FF simulations.

Conclusions:

• Polarizable force fields provide a more accurate representation of the membrane dielectric gradient's influence on permeation.
• Explicit dipole responses in polarizable FFs are crucial for understanding molecular transport.
• This study offers the first systematic quantification of polarizable FF impact in this context.