Analysis of hydrophobic and hydrophilic moments of short penetrating peptides for enhancing mitochondrial localization: prediction and validation

Pharmaceutical interest in targeting mitochondria is increasing because of their contribution in incurable diseases. However, the inner mitochondrial layer represents a major hurdle to overcome for most drugs. Penetrating peptides are a promising strategy for drug delivery, but the absence of standard principles and reliable prediction tools limits the design and discovery of sequences with improved organelle specificity. In our hypothesis, peptide local flexibility represents a valuable source to predict peptide performance. Here, a pool of short nonnatural peptides was designed with the same amino acid content but different positioning. Molecular dynamics and membrane-transfer simulations were used to generate the low-energy conformers in extra, intracellular, and membrane-inserted environments. The contributions of the hydrophobic and hydrophilic side chain–exposed surfaces revealed that the amino acid’s relative position significantly affected the simulated peptide’s dynamics. Based on the structural ...