Noncovalent Interaction Thresholds Control Translocation and Cytotoxicity: A Combined Computational-Experimental...

Area of Science:

• Computational Chemistry
• Molecular Dynamics
• Drug Design

Background:

• Cellular uptake of drugs is crucial for therapeutic efficacy.
• Noncovalent interactions significantly influence membrane permeability.
• Predicting and controlling drug-membrane interactions remains a challenge.

Purpose of the Study:

• To develop a molecular thermodynamic-dynamic (MTD) framework for quantifying interaction thresholds in membrane permeation.
• To establish design principles for optimizing drug permeability based on binding energy.
• To investigate the role of hydrogen (H-) and halogen (X-) bonding in membrane translocation.

Main Methods:

• Utilized a molecular thermodynamic-dynamic (MTD) framework.
• Employed polychlorinated biphenyls (PCBs) as molecular probes.
• Analyzed differential binding energy (ΔG) and its correlation with permeation coefficients.
• Identified transition states and rate-limiting steps in membrane translocation.

Main Results:

• Optimal membrane permeability is achieved within a specific differential binding energy range (ΔG = -3.6 to -6.8 kcal/mol).
• Excessive binding affinity (ΔG < -7.5 kcal/mol) results in kinetic trapping.
• A strong linear correlation (R² = 0.93) exists between permeation coefficients and differential binding energy.
• Identified a rate-limiting vertical rotation step (ΔG = 2.4 kcal/mol).

Conclusions:

• Intermediate differential binding energy (ΔG = -4.0 to -5.0 kcal/mol) maximizes drug permeability.
• This optimal range aligns with FDA-approved membrane-permeable drugs.
• Targeted modulation of X-bonding can precisely control membrane interaction specificity for drug design.