Molecular modeling of polynucleotide complexes

Area of Science:

• Biomedical Engineering
• Computational Biology
• Molecular Pharmacology

Background:

• Gene therapy utilizes polynucleotides (DNA or siRNA) for treating genetic disorders.
• Non-viral carriers like polymers and lipids are crucial for protecting polynucleotides and forming cell-permeable nanoparticles.
• Effective gene therapy relies on optimal nanoparticulate system formation, cellular uptake, and intracellular trafficking.

Purpose of the Study:

• To review molecular modeling research in gene therapy delivery.
• To identify knowledge gaps and propose future research directions.
• To elucidate atomic-level details of gene delivery systems inaccessible to experimental methods.

Main Methods:

• Review of existing molecular modeling studies on gene delivery.
• Analysis of computational approaches addressing cellular events in gene therapy.
• Discussion of limitations and future potential of molecular modeling.

Main Results:

• Molecular modeling has illuminated nanoparticle formation dynamics, carrier complexation, and polynucleotide release.
• Studies reveal carrier conformations during endosomal stages.
• Computational methods are beginning to address rate-limiting cellular events like internalization and endosomal escape.

Conclusions:

• Molecular modeling provides critical atomic-level insights into gene delivery mechanisms.
• Current limitations in computational power and model accuracy hinder realistic simulations.
• Advancements in computational power will enable better investigation of gene therapy and facilitate the design of novel therapeutics.